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Inflammation is a central pathogenic feature of the acute respiratory distress syndrome (ARDS) in COVID-19. Previous pathologies such as diabetes, autoimmune or cardiovascular diseases become risk factors for the severe hyperinflammatory syndrome. A common feature among these risk factors is the subclinical presence of cellular stress, a finding that has gained attention after the discovery that BiP (GRP78), a master regulator of stress, participates in the SARS-CoV-2 recognition. Here, we show that BiP serum levels are higher in COVID-19 patients who present certain risk factors. Moreover, early during the infection, BiP levels predict severe pneumonia, supporting the use of BiP as a prognosis biomarker. Using a mouse model of pulmonary inflammation, we observed increased levels of cell surface BiP (cs-BiP) in leukocytes during inflammation. This corresponds with a higher number of neutrophiles, which show naturally high levels of cs-BiP, whereas alveolar macrophages show a higher than usual exposure of BiP in their cell surface. The modulation of cellular stress with the use of a clinically approved drug, 4-PBA, resulted in the amelioration of the lung hyperinflammatory response, supporting the anti-stress therapy as a valid therapeutic strategy for patients developing ARDS. Finally, we identified stress-modulated proteins that shed light into the mechanism underlying the cellular stress-inflammation network in lungs.

Background. Obesity is associated with dyslipidemia, and excess body fat is associated with unfavorable levels of adipokines and markers of inflammation. The goal of research. To study the level of adipokines and markers of inflammation, their associations with unstable atherosclerotic plaques in men with coronary atherosclerosis on the background of abdominal obesity. Materials and methods. The study involved 82 men aged 40–77 years with coronary atherosclerosis after endarterectomy from the coronary arteries. We divided all men into two groups: 37 men (45.1%) with unstable atherosclerotic plaques, and 45 men (54.9%) who had stable plaques. Obesity was established at a BMI of ≥30 kg/m2. The levels of adipokines and markers of inflammation in the blood were determined by multiplex analysis. Results. In patients with obesity and unstable plaques, the levels of C-peptide, TNFa and IL-6 were 1.8, 1.6, and 2.8 times higher, respectively, than in patients with obesity and stable plaques. The chance of having an unstable plaque increases with an increase in TNFa by 49% in obese patients and decreases with an increase in insulin by 3% in non-obese patients. Conclusions. In men with coronary atherosclerosis and obesity, unstable atherosclerotic plaques in the coronary arteries are directly associated with the level of TNF-α.

Immune checkpoint inhibitors (ICI) have provided significant improvement in clinical outcomes for some patients with solid tumors. However, for patients with head and neck cancer, the response rate to ICI monotherapy remains low, leading to the exploration of combinatorial treatment strategies. In this preclinical study, we use an oncolytic adenovirus (Ad5/3) encoding hTNFα and hIL-2 and non-replicate adenoviruses (Ad5) encoding mTNFα and mIL-2 with ICI to achieve superior tumor growth control and improved survival outcomes. The in vitro effect of Ad5/3-E2F-D24-hTNFa-IRES-hIL-2 was characterized through analyses of virus replication, transgene expression and lytic activity using head and neck cancer patient derived cell lines. Mouse models of ICI naïve and refractory oral cavity squamous cell carcinoma were established to evaluate the local and systemic anti-tumor immune response upon ICI treatment with or without the non-replicative adenovirus encoding mTNFα and mIL-2. We delineated the mechanism of action by measuring the metabolic activity and effector function of CD3+ tumor infiltrating lymphocytes (TIL) and transcriptomic profile of the CD45+ tumor immune compartment. Ad5/3-E2F-D24-hTNFa-IRES-hIL-2 demonstrated robust replicative capability in vitro across all head and neck cell lines screened through potent lytic activity, E1a and transgene expression. In vivo, in both ICI naïve and refractory models, we observed improvement to tumor growth control and long-term survival when combining anti-PD-1 or anti-PD-L1 with the non-replicative adenovirus encoding mTNFα and mIL-2 compared to monotherapies. This observation was verified by striking CD3+ TIL derived mGranzyme b and interferon gamma production complemented by increased T cell bioenergetics. Notably, interrogation of the tumor immune transcriptome revealed the upregulation of a gene signature distinctive of tertiary lymphoid structure formation upon treatment of murine anti-PD-L1 refractory tumors with non-replicative adenovirus encoding mTNFα and mIL-2. In addition, we detected an increase in anti-tumor antibody production and expansion of the memory T cell compartment in the secondary lymphoid organs. In summary, a non-replicative adenovirus encoding mTNFα and mIL-2 potentiates ICI therapy, demonstrated by improved tumor growth control and survival in head and neck tumor-bearing mice. Moreover, the data reveals a potential approach for inducing tertiary lymphoid structure formation. Altogether our results support the clinical potential of combining this adenovirotherapy with anti-PD-1 or anti-PD-L1.

Introduction: Short-Chain Fatty Acids (SCFA) are products of intestinal microbial metabolism that can reach the brain and alter microglia in health and disease contexts. However, data are conflicting on the effect of acetate, the most abundant SCFA in the blood, in these cells. Objective: The authors aimed to investigate acetate as a modulator of the inflammatory response in microglia stimulated with LPS. Method: The authors used an immortalized cell line, C8-B4, and primary cells for in vitro treatments with acetate and LPS. Cell viability was analyzed by MTT, cytokine by RT-PCR, ELISA, and flow cytometry. The authors also performed in vivo and in silico analyses to study the role of acetate and the TNF-α contribution to the development of Experimental Autoimmune Encephalomyelitis (EAE). Results: Acetate co-administered with LPS was able to exacerbate the production of pro-inflammatory cytokines at gene and protein levels in cell lines and primary culture of microglia. However, the same effects were not observed when acetate was administered alone or as pretreatment, prior to the LPS stimulus. Additionally, pharmacological inhibition of histone deacetylase concomitantly with acetate and LPS led to decreased TNF-α production. In silico analysis showed a crucial role of the TNF-α pathway in EAE development. Moreover, acetate administration in vivo during the initial phase of EAE led to a better disease outcome and reduced TNF-α production. Conclusion: Treatment with acetate was able to promote the production of TNF-α in a concomitant LPS stimulus of microglia. However, the immune modulation of microglia by acetate pretreatment may be a component in the generation of future therapies for neurodegenerative diseases. HIGHLIGHTS Acetate was able to exacerbate the production of TNF-α in microglia. Acetate administered as pre-treatment to LPS acts as an anti-inflammatory. Histone deacetylase decreased TNF-α production in Acetate- and LPS-treated cells. Depending on the time of administration, Acetate modulates microglia’s activation. Acetate may threaten neurodegenerative and neuropsychiatric diseases.

Background Tumor necrosis factor alpha (TNFA) is an important cytokine that influences multiple biological processes. It is one of the key mediators of acute and chronic systemic inflammatory reactions and plays a central role in several autoimmune diseases. A number of approved monoclonal antibodies (mAbs) are widely used to subside these autoimmune diseases. However, there is a high rate of non-responsiveness to treatments with these mAbs. Therefore, it is important to be able to predict responses of the patients in an individualistic manner to these therapeutic antibodies before administration. In the present study, we used in silico tools to explore the effects of missense variants in the respective epitopes of four therapeutic anti-TNFA mAbs—adalimumab (ADA), certolizumab pegol (CZP), golimumab (GLM), and infliximab (IFX)—on their interactions with TNFA. Results The binding affinities of CZP and ADA to corresponding epitopes appear to be reduced by four (TNFAR131Q, TNFAE135G, TNFAR138Q, and TNFAR138W) and two (TNFAG66C and TNFAG66S) variants, respectively. The binding of GLM and IFX appears to be affected by TNFAR141S and TNFAR138W, respectively. TNFAG66C and TNFAG66S may be associated with autoimmune diseases, whereas TNFAE135G, TNFAR138W, and TNFAR141S may be pathogenic per se. Conclusion These variants may contribute to the observed inter-individual variability in response to anti-TNFA mAbs treatments and be used as markers to predict responses, and thus optimize therapeutic benefits to the patients.

Tumor necrosis factor (TNF)-α is a proinflammatory cytokine that plays an important role in the pathogenesis of autoimmune diseases. The aim of the study was to establish an association between TNF-α promoter variability and systemic sclerosis (SSc). The study included 43 SSc patients and 74 controls. Four single nucleotide polymorphisms (rs361525, rs1800629, rs1799724, and rs1799964) located at the promoter of the TNFA gene were genotyped using commercially available TaqMan allelic discrimination assays with real-time PCR. The rs1799724 allele was associated with an increased SSc susceptibility (p = 0.028). In turn, none of the polymorphisms studied were related to the clinical and laboratory parameters of SSc patients, except for a higher prevalence of anti-Ro52 antibodies in the AG rs1800629 genotype in comparison to GG carriers (p = 0.04). Three of four cancer patients had both CT rs1799964 and AG rs361525 genotypes; thus, both of them were related to the increased risk of cancer, as compared to the TT (p = 0.03) and GG carriers (p = 0.0003), respectively. The TNFA C rs1799724 variant is associated with an increased risk of SSc, while the CT rs1799964 and AG rs361525 genotypes might enhance cancer susceptibility in SSc patients, although large observational and experimental studies are needed to verify the above hypothesis.

Intratumoral immunotherapies are entering clinical use but concerns remain regarding their effects on non-injected tumors. Here, we studied the impact of local treatment with an adenovirus coding for TNFa and IL-2 on systemic antitumor response in animals receiving aPD-1 (anti-programmed cell death protein 1) therapy. Using bilateral murine melanoma models, we tested systemic tumor response to combined therapy with anti-PD-1 and an adenovirus coding for TNFa and IL-2 ("virus"). Virus was given intratumorally (to one of the two tumors only) and aPD-1 monoclonal antibody systemically. We evaluated both tumors' response to treatment, overall survival, metastasis development, and immunological mechanisms involved with response. Consistent tumor control was observed in both injected and non-injected tumors, including complete response in all treated animals receiving aPD-1+ virus therapy. Mechanistically, virus injections enabled potent effector lymphocyte response locally, with systemic effects in non-injected tumors facilitated by aPD-1 treatment. Moreover, adenovirus therapy demonstrated immunological memory formation. Virus therapy was effective in preventing metastasis development. Local treatment with TNFa and IL-2 coding adenovirus enhanced systemic response to aPD-1 therapy, by re-shaping the microenvironment of both injected and non-injected tumors. Therefore, our pre-clinical data support the rationale for a trial utilizing a combination of aPD-1 plus virus for the treatment of human cancer.

Osteoarthritis (OA) occurs not only in the knee but also in peripheral joints throughout the whole body. Previously, we have shown that the expression of cellular communication network factor 3 (CCN3), a matricellular protein, increases with age in knee articular cartilage, and the misexpression of CCN3 in cartilage induces senescence-associated secretory phenotype (SASP) factors, indicating that CCN3 promotes cartilage senescence. Here, we investigated the correlation between CCN3 expression and OA degenerative changes, principally in human femoral head cartilage. Human femoral heads obtained from patients who received total hip arthroplasty were categorized into OA and femoral neck fracture (normal) groups without significant age differences. Gene expression analysis of RNA obtained from femoral head cartilage revealed that CCN3 and MMP-13 expression in the non-weight-bearing part was significantly higher in the OA group than in the normal group, whereas the weight-bearing OA parts and normal cartilage showed no significant differences in the expression of these genes. The expression of COL10A1, however, was significantly higher in weight-bearing OA parts compared with normal weight-bearing parts, and was also higher in weight-bearing parts compared with non-weight-bearing parts in the OA group. In contrast, OA primary chondrocytes from weight-bearing parts showed higher expression of CCN3, p16, ADAMTS4, and IL-1β than chondrocytes from the corresponding normal group, and higher ADAMTS4 and IL-1β in the non-weight-bearing part compared with the corresponding normal group. Acan expression was significantly lower in the non-weight-bearing group in OA primary chondrocytes than in the corresponding normal chondrocytes. The expression level of CCN3 did not show significant differences between the weight-bearing part and non-weight-bearing part in both OA and normal primary chondrocytes. Immunohistochemical analysis showed accumulated CCN3 and aggrecan neoepitope staining in both the weight-bearing part and non-weight-bearing part in the OA group compared with the normal group. The CCN3 expression level in cartilage had a positive correlation with the Mankin score. X-ray analysis of cartilage-specific CCN3 overexpression mice (Tg) revealed deformation of the femoral and humeral head in the early stage, and immunohistochemical analysis showed accumulated aggrecan neoepitope staining as well as CCN3 staining and the roughening of the joint surface in Tg femoral and humeral heads. Primary chondrocytes from the Tg femoral head showed enhanced expression of Ccn3, Adamts5, p16, Il-6, and Tnfα, and decreased expression of Col2a1 and -an. These findings indicate a correlation between OA degenerative changes and the expression of CCN3, irrespective of age and mechanical loading. Furthermore, the Mankin score indicates that the expression level of Ccn3 correlates with the progression of OA.

Oral carcinogenesis represents a multi-stage process which encompasses several genetic and molecular changes that promote the progression of oral potentially malignant disorders (OPMDs) to oral squamous cell carcinomas (OSCCs). A better understanding of critical pathways governing the progression of OMPDs to OSCCs is critical to improve oncologic outcomes in the future. Previous studies have identified an important role of tumor necrosis factor α (TNFα) and TNF receptor 1 (TNFR1) in the invasiveness of oral cancer cell lines. Here, we investigate the expression of TNFα and TNFR1 in human OPMDs that progress to OSCC compared to non-progressing OPMDs utilizing fluorescent immunohistochemistry (FIHC) to show increased TNFα/TNFR1 expression in progressing OPMDs. In order to interrogate the TNFα/TNFR1 signaling pathway, we utilized a 4-nitroquinoline 1-oxide (4-NQO) mouse model of oral carcinogenesis to demonstrate that TNFα/TNFR1 expression is upregulated in 4-NQO-induced OSCCs. TNFα neutralization decreased serum cytokines, inhibited the development of invasive lesions and reduced tumor-associated neutrophils in vivo. Combined, this data supports the role of TNFα in oral malignant transformation, suggesting that critical immunoregulatory events occur downstream of TNFR1 leading to malignant transformation. Our results advance the understanding of the mechanisms governing OSCC invasion and may serve as a basis for alternative diagnostic and therapeutic approaches to OPMDs and OSCC management.

Yuanyuan Li,1,* Yueqi Song,1,* Leqing Zhu,1,* Xiao Wang,1 Bin Yang,2 Ping Lu,2 Quan Chen,3 Lianghua Bin,4 Liehua Deng5 1Biomedical Translational Research Institute, The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong Province, People’s Republic of China; 2Department of Dermatology, Dermatology Hospital of Southern Medical University, Guangzhou, Guangdong Province, People’s Republic of China; 3Division of Research Informatics Services, Department of Medicine, National Jewish Health, Denver, CO, USA; 4Department of Pediatrics, National Jewish Health, Denver, CO, USA; 5Department of Dermatology, The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lianghua BinDepartment of Pediatrics, National Jewish Health, 1400 Jackson Street, Denver, CO 80206, USATel +1-303-270-2055Email binl@njhealth.orgLiehua DengDepartment of Dermatology, The First Affiliated Hospital, Jinan University, West Huangpu Dadao, No 605, Tianhe Qu, Guangzhou, Guangdong Province, People’s Republic of ChinaTel +86-137-25356728Email liehuadeng@126.comPurpose: There is increased type I interferon signature in psoriasis patients. Interferon-kappa (IFN-κ) is a member of type I interferon family that is constitutively expressed by keratinocytes. In this study, we investigate whether IFN-κ is involved in psoriasis etiology.Patients and methods: Twenty healthy individuals, 20 psoriasis vulgaris patients and 10 atopic dermatitis (AD) were included for this study. Immunohistochemistry staining, normal human epidermal keratinocytes (NHEK) culture, Ca2Cl-induced differentiation, quantitative reverse transcription (qRT-PCR), ELISA and murine experiments were performed.Results: We found IFN-κ protein expression was extremely low in the epidermis of normal skin, but it was significantly increased in the suprabasal layers of epidermal keratinocytes in psoriatic skin lesions. However, its expression in the skin lesions of AD was similar to normal skin. Additionally, IFN-κ protein was detected in sera from psoriasis patients, but not in sera from normal subjects and AD. We further investigated the regulation of IFNk gene expression in NHEK. We found that IFNk was significantly induced by types of nucleic acid pathogen recognition receptor (PRR) agonists in NHEK. While its expression was significantly induced by itself and IFN-γ, it was inhibited by type 2 immunity cytokines IL4 and IL13; other inflammatory cytokines including IL1 super-family members and IL17A did not alter its expression. Addition of recombinant IFN-κ did not affect keratinocytes differentiation. Using the murine experimental model, we demonstrated that subcutaneous administration of recombinant IFN-κ did not increase skin thickness, but significantly increased the transcription of TNFA and IL17A in mice skin.Conclusion: Increased IFN-κ in psoriasis may be caused by injured cells-released nucleic acids, increased IFN-γ and self-activation. Its enhancement may contribute to the etiology of the disease by enhancing TNFA and IL17A gene expression.Keywords: IFN-κ, psoriasis, TNFA, IL17A, atopic dermatitis

Yuanyuan Li,1,* Yueqi Song,1,* Leqing Zhu,1,* Xiao Wang,1 Bin Yang,2 Ping Lu,2 Quan Chen,3 Lianghua Bin,4 Liehua Deng5 1Biomedical Translational Research Institute, The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong Province, People’s Republic of China; 2Department of Dermatology, Dermatology Hospital of Southern Medical University, Guangzhou, Guangdong Province, People’s Republic of China; 3Division of Research Informatics Services, Department of Medicine, National Jewish Health, Denver, CO, USA; 4Department of Pediatrics, National Jewish Health, Denver, CO, USA; 5Department of Dermatology, The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lianghua BinDepartment of Pediatrics, National Jewish Health, 1400 Jackson Street, Denver, CO 80206, USATel +1-303-270-2055Email binl@njhealth.orgLiehua DengDepartment of Dermatology, The First Affiliated Hospital, Jinan University, West Huangpu Dadao, No 605, Tianhe Qu, Guangzhou, Guangdong Province, People’s Republic of ChinaTel +86-137-25356728Email liehuadeng@126.comPurpose: There is increased type I interferon signature in psoriasis patients. Interferon-kappa (IFN-κ) is a member of type I interferon family that is constitutively expressed by keratinocytes. In this study, we investigate whether IFN-κ is involved in psoriasis etiology.Patients and methods: Twenty healthy individuals, 20 psoriasis vulgaris patients and 10 atopic dermatitis (AD) were included for this study. Immunohistochemistry staining, normal human epidermal keratinocytes (NHEK) culture, Ca2Cl-induced differentiation, quantitative reverse transcription (qRT-PCR), ELISA and murine experiments were performed.Results: We found IFN-κ protein expression was extremely low in the epidermis of normal skin, but it was significantly increased in the suprabasal layers of epidermal keratinocytes in psoriatic skin lesions. However, its expression in the skin lesions of AD was similar to normal skin. Additionally, IFN-κ protein was detected in sera from psoriasis patients, but not in sera from normal subjects and AD. We further investigated the regulation of IFNk gene expression in NHEK. We found that IFNk was significantly induced by types of nucleic acid pathogen recognition receptor (PRR) agonists in NHEK. While its expression was significantly induced by itself and IFN-γ, it was inhibited by type 2 immunity cytokines IL4 and IL13; other inflammatory cytokines including IL1 super-family members and IL17A did not alter its expression. Addition of recombinant IFN-κ did not affect keratinocytes differentiation. Using the murine experimental model, we demonstrated that subcutaneous administration of recombinant IFN-κ did not increase skin thickness, but significantly increased the transcription of TNFA and IL17A in mice skin.Conclusion: Increased IFN-κ in psoriasis may be caused by injured cells-released nucleic acids, increased IFN-γ and self-activation. Its enhancement may contribute to the etiology of the disease by enhancing TNFA and IL17A gene expression.Keywords: IFN-κ, psoriasis, TNFA, IL17A, atopic dermatitis

Mitochondrial dloop and nuclear tnfa II sequences were sequenced from brown trout collected in the Vesta River (Italian Alps), situated in the middle of a Pleistocene ice free refugia area east of the Lake Garda. Haplotypes belonging to the native Adriatic lineage were mixed with other from the Atlantic and Marble lineages. A probabilistic approach, based on simulations, indicated the likelihood of a past introgression of Atlantic haplotypes into native populations belonging to the Adriatic lineage. These results argue in favor of a past natural presence of brown trout in the Italian Alps, in particular in ice free refugia areas, which have been almost completely wiped out by the massive and extensive introduction of Atlantic hatchery stocks.

Objective: Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that mainly targets joints. Monocytes and macrophages are critical in RA pathogenesis and contribute to inflammatory lesions. These extremely plastic cells respond to extracellular signals which cause epigenomic changes that define their pathogenic phenotype. Here, we interrogated how DNA methylation alterations in RA monocytes are determined by extracellular signals. Methods: High-throughput DNA methylation analyses of patients with RA and controls and in vitro cytokine stimulation were used to investigate the underlying mechanisms behind DNA methylation alterations in RA as well as their relationship with clinical parameters, including RA disease activity. Results: The DNA methylomes of peripheral blood monocytes displayed significant changes and increased variability in patients with RA with respect to healthy controls. Changes in the monocyte methylome correlate with DAS28, in which high-activity patients are divergent from healthy controls in contrast to remission patients whose methylome is virtually identical to healthy controls. Indeed, the notion of a changing monocyte methylome is supported after comparing the profiles of same individuals at different stages of activity. We show how these changes are mediated by an increase in disease activity-associated cytokines, such as tumour necrosis factor alpha and interferons, as they recapitulate the DNA methylation changes observed in patients in vitro. Conclusion: We demonstrate a direct link between RA disease activity and the monocyte methylome through the action of inflammation-associated cytokines. Finally, we have obtained a DNA methylation-based mathematical formula that predicts inflammation-mediated disease activity for RA and other chronic immune-mediated inflammatory diseases., We thank CERCA Programme/Generalitat de Catalunya for institutional support. EB was funded by the Spanish Ministry of Economy and Competitiveness (MINECO; grant numbers SAF2014-55942-R and SAF2017-88086-R). JDC was funded by FIS grant (PI17/00993) from Institute of Health Carlos III (ISCIII). JDC, JM and EB are supported by RETICS network grant from ISCIII (RIER, RD16/0012/0013), FEDER 'Una manera de hacer Europa'

Immune system dysregulation plays a role in the pathogenesis of complex human diseases, including psychiatric disorders. In addition, elevated levels of pro-inflammatory cytokines, including tumor necrosis factor α (TNF-α) may be conditioned by the presence of specific polymorphic variants. The present case-controlled preliminary study evaluated the prevalence of TNFA gene single nucleotide polymorphisms (SNPs) G-308A (rs1800629) and T-1031C (rs1799964) in 83 Polish patients with depression by restriction fragment length polymorphism analysis. The results were compared with the frequencies of genotypes in a geographically- and ethnically-matched group of individuals without depression. No statistically significant difference in genotype/allele frequency was observed for either SNP between the two groups. No association was found between the particular genotypes and selected demographic/clinical features, including sex, age at diagnosis or severity of depressive symptoms before/after pharmacotherapy. Thus, there does not appear to be any connection between the studied SNPs and the development and progression of depression; however, further studies are required with larger cohorts to better understand this aspect of depression.

Activation of transposable elements (TEs) can cause cellular damage. Cytoplasmic nucleic acid sensing pathways evolved to detect pathogens, but can also serve to cull cells with inappropriate TE activation as TEs can be viral mimetics. Epigenetic silencing of TEs is mediated in part by DNA methylation, but it is not clear if TE activation or the immune system contribute to the cellular damage caused by loss of DNA methylation. Here, we provide mechanistic insight into the observation of an activated interferon response in the liver of zebrafish larvae with deletion in critical components of the DNA methylation machinery, uhrf1 and dnmt1. We focus on dissecting the relationship between DNA methylation, TE activation and induction of an immune response through cytoplasmic DNA and double stranded RNA sensing pathways and identify tnfa as a mediator of cell death in the liver of these mutants. Integrated RNAseq and methylome analysis identified LTR transposons as the most upregulated in these mutants and also the most methylated in control larvae, indicating a direct role of DNA methylation in suppressing this TE subclass. RNAseq analysis from these same samples revealed expression signatures of a type-I interferon response and of tnfa activation, mimicking the pattern of gene expression in virally infected cells. CRISPR/Cas9 mediated depletion of the cellular antiviral sensors sting and mavs reduced expression of interferon response genes and tnfa depletion dramatically reduced cell death in uhrf1 mutant livers. This suggests that the antiviral response induced by DNA hypomethylation and TE activation in the liver is mediated by the signaling pathways activated by both cytoplasmic double stranded RNA and DNA and that tnfa mediates cell death as a potential mechanism to eliminate these damaged cells.

The aim of this study was to evaluate the effect of dietary polyphenols on the expression of the effectors involved in inflammation and apoptosis in rabbit ovary. New Zealand White female rabbits were fed a basal control diet (CTR), or the same diet supplemented with a polyphenolic concentrate (POL, 282.4 mg/kg) obtained from olive mill waste waters. The follicle counts and the relative mRNA (RT-qPCR) and protein (immunohistochemistry) expression of the effectors involved in inflammation (cyclooxygenase-2, interleukin-1beta, tumor necrosis factor-alpha, TNFA) and apoptosis (BCL2-associated X protein, BAX), detected in the ovaries of both groups, were examined. The POL diet increased the primary and total follicles number. Cyclooxygenase-2 gene expression was higher (p &lt, 0.05) in the POL group than in the CTR group, whereas BAX was lower (p &lt, 0.05) in POL than CTR. Immunohistochemistry revealed the presence of all the proteins examined, with weaker (p &lt, 0.05) COX2 and BAX signals in POL. No differences between the CTR and POL groups were observed for IL1B and TNFA gene and protein expression. These preliminary findings show that dietary polyphenols modulate inflammatory and apoptotic activities in rabbit ovary, regulating cyclooxygenase-2 and BAX expression, thus suggesting a functional involvement of these dietary compounds in mammalian reproduction.

Temporal lobe epilepsy is a widespread chronic disorder that manifests as spontaneous seizures and is often characterized by refractoriness to drug treatment. Temporal lobe epilepsy can be caused by a primary brain injury, therefore, the prevention of epileptogenesis after a primary event is considered one of the best treatment options. However, a preventive treatment for epilepsy still does not exist. Neuroinflammation is directly involved in epileptogenesis and neurodegeneration, leading to the epileptic condition and cognitive decline. In the present study, we aimed to clarify the effect of treatment with a recombinant form of the Interleukin-1 receptor antagonist (anakinra) on epileptogenesis and behavioral impairments in rats using the lithium&ndash, pilocarpine model. We found that anakinra administration during the latent phase of the model significantly suppressed the duration and frequency of spontaneous recurrent seizures in the chronic phase. Moreover, anakinra administration prevented some behavioral impairments, including motor hyperactivity and disturbances in social interactions, during both the latent and chronic periods. Histological analysis revealed that anakinra administration decreased neuronal loss in the CA1 and CA3 areas of the hippocampus but did not prevent astro- and microgliosis. The treatment increased the expression level of the solute carrier family 1 member 2 gene (Slc1a2, encoding excitatory amino acid transporter 2 (EAAT2)) in the hippocampus, potentially leading to a neuroprotective effect. However, the increased gene expression of proinflammatory cytokine genes (Interleukin-1&beta, (Il1b) and tumor necrosis factor &alpha, (Tnfa)) and astroglial marker genes (glial fibrillary acidic protein (Gfap) and inositol 1,4,5-trisphosphate receptor type 2 (Itpr2)) in experimental rats was not affected by anakinra treatment. Thus, our data demonstrate that the administration of anakinra during epileptogenesis has some beneficial disease-modifying effects.

Mutations in MECP2 cause Rett syndrome, a severe neurological disorder with autism-like features. Duplication of MECP2 also causes severe neuropathology. Both diseases display immunological abnormalities that suggest a role for MeCP2 in controlling immune and inflammatory responses. Here, we used mecp2-null zebrafish to study the potential function of Mecp2 as an immunological regulator. Mecp2-deficiency resulted in an increase in neutrophil infiltration and upregulated expression of the pro- and anti-inflammatory cytokines Il1b and Il10 as a secondary response to disturbances in tissue homeostasis. In contrast, expression of the pro-inflammatory cytokine tumor necrosis factor alpha (Tnfa) was consistently downregulated in mecp2­-null animals during development, representing the earliest developmental phenotype described for MeCP2-deficiency to date. Expression of tnfa was unresponsive to inflammatory stimulation, and was partially restored by re-expression of functional mecp2. Thus, Mecp2 is required for tnfa expression during zebrafish development and inflammation. Finally, RNA sequencing of mecp2-null embryos revealed dysregulated processes predictive for Rett syndrome phenotypes.

The water buffalo is a fundamental resource, especially in developing countries, however, differently from other species, its genetic potential is still poorly investigated. In this work, we performed a candidate gene association study for milk composition in 491 female buffaloes. Animals were from four farms located in Southern Italy, where the Out-of-Breeding-Season-Mating technique is usually performed. We analysed three genes: (1) the signal transducer and activator of transcription 5A (STAT5A), (2) the tumour necrosis factor alpha (TNFα) and (3) the melatonin receptor 1A (MTNR1A). We confirmed the mutation at the MTNR1A gene and we found five novel single nucleotide polymorphisms (SNPs): one in the TNFα and four in the STAT5A. No associations were found for the SNPs in the MTNR1A and TNFα genes, while we identified a marked association with milk protein % for a C > T substitution at the STAT5A gene. At this locus, the TT buffaloes showed significantly higher protein percentage in milk. Conversely, this genotype class was the less frequent in the population. Moreover, an A > G substitution at the STAT5A showed an influence on reproductive seasonality, with the advantageous allele most frequent in the population, suggesting a possible effect of selection for this trait. The C > T substitution on STAT5A detected in present study could be used in marker assisted selection of Mediterranean Italian buffalo, and should be monitored to understand the reasons behind the low frequency of the favourable genotype at this locus and to stop this unfavourable trend in the population.

The present article discusses the characteristics and significance of content violation of key pro-inflammatory cytokines IL-8, TNFa, MCP-1 and key anti-inflammatory cytokine IL-10 during pro-inflammatory stage in patients with chronic heart failure (CHF), determined by dilated cardiomyopathy (31 patient) and in CHF patients with coronary heart disease (CHD) (29 patients). EIA method with enzyme immune test systems (ZAO "Vector Best") and analyser ACCESS was used to assess the content of cytokines in the blood. The results of the study showed significant reduction of IL-8, increase of TNFa, MCP-1 and IL-10. Violation of adequate response of cytokines in pro-inflammatory stage enables to consider this disorder as a pathogenic unfavorable factor, leading to CHF progression in patients with dilated cardiomyopathy and CHD. Comparison of the parameters of cardiac hemodynamics, differential white blood cell count and correlation results proves that heart failure in patients with dilated cardiomyopathy and CHD have similar pathogenic origins of chronic inflammatory process. Imbalance of IL-8, TNFa, MCP-1 and IL-10 does not provide protection from inflammatory and bacterial antigens. In case of inadequate and protracted inflammatory reaction, decreased cytokine-producing leukocyte function can destroy myocardium. Results of correlation analysis prove violation of linear connection andformation of atypical correlations between TNFa and TNFa monocytes and neutrophils, IL-8 and monocytes, TNFa and IL-10, IL-10 and lymphocytes, IL-10 and TNFa, IL-8 and IL-10. Increased production of TNFa, MCP-1 in combination with decreased IL-8 and increased IL-10 indicates staging violation accompanied by delay of transition of pro-inflammatory stage into anti-inflammatory one.

Muscle-invasive bladder cancer (MIBC) is an aggressive form of urothelial bladder carcinoma (UBC) with poorer outcomes compared to the non-muscle invasive form (NMIBC). Higher recurrent rates and rapid progression after relapse in UBC is known to be linked with chronic inflammation. Here, the preclinical murine models of NMIBC (MB49) and MIBC (MB49-I) were used to assess the antitumor effects of DAB-1, an anti-inflammatory aminobenzoic acid derivative we have developed in order to target cancer-related inflammation. A subchronic toxicity study on cancer-free mice shown that DAB-1 treatment did not affect normal mouse development or normal function of vital organs. In mice bearing MB49-I tumors, whole body accumulation of the radioconjugate [ 131I]DAB-1 was higher than in control mice, the main sites of [131I]DAB-1 accumulation being the liver (34%), the intestines (21%), and the tumors (18%). In vivo molecular therapy of ectopic and orthotopic tumors indicated that treatment with DAB-1 efficiently inhibited tumor growth, metastasis formation, and mortality rate. The antitumor efficacy of DAB-1 was associated with strong decreased tumor cell proliferation and iNOS expression in tumor tissues and deactivation of macrophages from tumor-bearing mice. Mechanistic investigations revealed that DAB-1 efficiently inhibited i) TNFα/NFΚB and IL6/STAT3 signaling pathways activation; ii) TNFα-induced NO production by decreasing NFΚB transcriptional activation and functional iNOS expression; and iii) cellular proliferation with minimal or no effects on cell mortality or apoptosis. In conclusion, this study provides preclinical and biological/mechanistic data highlighting the potential of DAB-1 as a safe and efficient therapeutic agent for the treatment of patients with NMIBC and MIBC. Fil: Girouard, Julie. Université du Québec a Montreal; Canadá Fil: Belgorosky, Denise. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina Fil: Hamelin Morrissette , Jovane. Université du Québec a Montreal; Canadá Fil: Boulanger, Valerie. Université du Québec a Montreal; Canadá Fil: D'Orio, Ernesto. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina Fil: Ramla, Djamel. Université du Québec a Montreal; Canadá Fil: Perron, Robert. Université du Québec a Montreal; Canadá Fil: Charpentier, Lucie. Université du Québec a Montreal; Canadá Fil: Van Themsche, Celine. Université du Québec a Montreal; Canadá Fil: Eijan, Ana Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina Fil: Bérubé, Gervais. Université du Québec a Montreal; Canadá Fil: Reyes Moreno, Carlos. Université du Québec a Montreal; Canadá

Fragestellung: Nach traumatischen Knorpelverletzungen führen sowohl nekrotische als auch apoptotische Prozesse zum progressiven Zellverlust, welcher eine entscheidende Rolle bei der Knorpeldegeneration spielt. Ziel dieser Arbeit war die Untersuchung der programmierten Nekrose (=Nekroptose)[zum vollständigen Text gelangen Sie über die oben angegebene URL], Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2019)

Background Functional variants ‐173 G > C (rs755622) and ‐794CATT5‐8 (rs5844572) MIF gene have been associated with the risk in several types of cancer, as well as with the increase of soluble levels of MIF and TNFα. However, in previous studies contradictory and uncertain results have been presented on the implication of MIF polymorphisms with the association in cancer, specifically in breast cancer (BC). We investigated whether the variants are associated with the susceptibility to develop BC and the soluble levels of MIF and TNFα in women with BC from western Mexico. Materials and methods A total of 152 women with BC and 182 control subjects (CS) were enrolled in this study. The determination of genotypes ‐173 G > C and ‐794 CATT5‐8 MIF polymorphisms was performed by PCR‐RFLP and PCR, respectively. In addition, the soluble levels of MIF and TNFα in both studied groups were quantified by ELISA and MILLIPLEX assay, respectively. Results The most frequent allele found in BC was the G (74.3%) and 6 (54%) in the variants ‐173G > C and ‐794 CATT5‐8, respectively, without significant differences in both groups. Nevertheless, the women with BC carriers ‐173*C and ‐794CATT7 have higher levels of MIF in comparison with CS. An increase of MIF (BC: 11.1 ng/mL vs CS: 5.2 ng/mL, P

There are inconsistent findings in the literature about the directionality and magnitude of the association between inflammation and depressive symptoms. This study separates predictors into between-person and within-person components in an attempt to gain greater clarity about this relationship. Blood samples were collected and depressive symptoms assessed in 140 adolescents (54% female, 59% Black, Mage = 16.1 years) with at least three blood draws and a total of 394 follow-up evaluations. Multi-level modeling indicated that the within-person effect of TNF-α predicted future total depressive symptoms, suggesting a potential causal relationship. Additionally, there were bidirectional, between-person effects of IL-6 on total depressive symptoms and vice-versa. Exploratory analyses examined the associations between five biomarkers and five subsets of depressive symptoms. These findings inform modeling decisions that may explain inconsistencies in the extant literature as well as suggest potential causal relationships between certain biomarkers with significant within-person effects on depressive symptoms, and vice-versa.

Fish Red-Blood Cells (RBCs) are nucleated cells that can modulate the expression of different sets of genes in response to stimuli, playing an active role in the homeostasis of the fish immune system. Nowadays, vaccination is one of the main ways to control and prevent viral diseases in aquaculture and the development of novel vaccination approaches is a focal point in fish vaccinology. One of the strategies that has recently emerged is the use of nanostructured recombinant proteins. Nanostructured cytokines have already been shown to immunostimulate and protect fish against bacterial infections. To explore the role of RBCs in the immune response to two nanostructured recombinant proteins, TNFa and a G-VHSV protein fragment, we performed different in vitro and in vivo studies. We show for the first time that rainbow trout RBCs are able to endocytose nanostructured TNFa and G-VHSV protein fragment in vitro, despite not being phagocytic cells, and in response to nanostructured TNFa and G-VHSV fragment, the expression of different immune genes could be modulated. This work was supported by the European Research Council fund to MO-V (ERC Starting Grant GA639249) and by grants from the Spanish Ministry of Science, European commission and AGAUR funds to NR (AGL2015-65129-R MINECO/FEDER and 2014SGR- 345 AGAUR). RT holds a pre-doctoral scholarship from AGAUR (Spain).

Background:\ud Two current theories regarding the neuroscientific bases of mood disorders involve alterations in glutamatergic neurotransmission and excessive activation of inflammatory pathways. We hypothesized that glutamate (Glu) levels and peripheral inflammatory markers would be associated with cognitive function, in patients with Bipolar Disorder Type II (BP-II), and that such factors would be associated with psychological treatment outcomes. \ud \ud Aims: \ud The primary aim of this study was to explore the relationship between the neurotransmitter Glu, cytokines (CRP, IL_6, and TNFa) and neuropsychological and related functioning. The secondary aim was to assess cognitive functioning as a predictor of poor response to psychological therapy. \ud \ud Methods: \ud Proton magnetic resonance spectroscopy data were acquired from the anterior cingulate cortex (ACC) of 15 participants with BP-II, and 13 healthy controls in a 3T magnetic resonance imaging scanner. The Digit Symbol Task (DST) for processing speed, TMT-B for executive function and Rey Auditory Verbal Learning Test (RAVLT) were administered to assess cognitive domains. \ud \ud Results: \ud There was no significant difference in anterior cingulate Glu, or inflammatory markers between groups. Furthermore, we found no significant difference between groups in any cognitive tests. Scores on the DST were found to be significantly associated with poor response to psychological therapy. \ud \ud Conclusions: \ud This study may highlight an association between neuropsychological dysfunction and treatment outcome in euthymic patients with BP-II. We did not find any association between peripheral inflammatory markers and brain Glu levels. This may have been in part due to the small sample size.

Hintergrund Dialysepflichtige Patienten mit fortgeschrittenem, chronischem Nierenversagen haben eine hohe Morbidität und Mortalität aufgrund häufiger kardio-vaskulärer Ereignisse. Traditionell mit diesem Krankheitsbild assoziierte Risikofaktoren wie Dyslipidämie und arterielle Hypertonie erklären dies nur unzureichend. Dialysepatienten zeigen einen beschleunigten arteriosklerotischen Gefäßumbau und arterielle Gefäßmineralisierung, welche die Funktionalität der Gefäße stark beeinträchtigen. Der pathologische Prozess der osteo-chrondroblastären Transition und nachfolgenden Mineralisierung von humanen glatten Gefäßmuskelzellen (VSMCs) in der arteriellen Tunica Media wird möglicherweise durch Urämietoxine ausgelöst, die sich bei Dialysepatienten vermehrt im Blut ansammeln. In der vorliegenden Arbeit wurden zugrundeliegende, molekulare Mechanismen dieser Mineralisierung aufgeklärt, um neue Behandlungsstrategien zu entwickeln. Methodik Urämische Seren von 14 Dialysepatienten, die im Rahmen der „Permeability Enhancement to Reduce Chronic Inflammation“ (PERCI-I)-Studie rekrutiert worden waren, wurden auf die proinflammatorischen Biomarker Tumor-Nekrose-Faktor-alpha (TNF-α) und Interleukin-6 (IL-6) als Mediatoren urämieinduzierter Inflammation mittels ELISA getestet und mit Seren gesunder Kontrollen verglichen. Mechanistische Untersuchungen zur transkriptionellen Regulation von IL-6 erfolgten mittels Promotor-Deletions-Analysen und Elektro-Mobility-Shift-Assays in VSMCs, die mit gepoolten urämischen bzw. Kontrollseren oder TNF-α stimuliert wurden. Die Spezifität des dabei identifizierten Transkriptionsfaktors wurde durch pharmakologische Inhibierungsexperimente überprüft und Westernblots zur Untersuchung der upstream Singnaltransduktion abgeschlossen. Spezifische - an der osteochondroblastären Transition beteiligte - Gene wurden mittels real-time PCR analysiert. Alkalische Phosphatase-messungen und Kalzifizierungsassays dienten zur funktionellen Untersuchung der VSMC-Mineralisierung. Ergebnisse Im Vergleich zu gesunden Kontrollen zeigten Seren urämischer Patienten signifikant erhöhte Spiegel von TNF-α und IL-6. In VSMCs induzierte urämisches Serum eine TNF-α-abhängige IL-6-Induktion sowie eine osteochondoblastäre Transition und signifikante Mineralisierung. Dies wurde über die extrazelluläre-signal-regulierte Kinase-1 (ERK-1) und den Aktivierungs-Protein-1 (AP-1) / c-FOS-Transkriptionsfaktorkomplex vermittelt, welcher im IL-6-Promotor bindet. Die pharmakologische Inhibition von TNF-α, IL-6, ERK-1 und AP-1/cFOS reduzierte die osteochondroblastäre Transition und Mineralisierung und verbesserte das Zellüberleben. Schlussfolgerung Die urämiebedingte, chronische Inflammation bei Dialysepatienten geht mit einer systemischen Erhöhung von TNFα und IL-6 einher. Insbesondere die TNF-α-induzierte IL-6-Produktion in VSMCs wurde als neuer entscheidender Faktor der vaskulären Mineralisierung in VSMCs identifiziert. Eine auf den spezifischen Patienten abgestimmte, pharmakologische Blockade von TNF-α und IL-6 könnte somit neben dem Einsatz neuartiger Dialysemembranen mit verbesserter Elimination urämischer Toxine eine interessante, neuartige Therapieoption zur Reduktion der Gefäßmineralisierung bei Hämodialysepatienten darstellen., Introduction Patients under dialysis-treatment for end-stage renal disease (ESRD) display a highly increased cardio-vascular morbidity and mortality but risk-factors traditionally associated with ESRD such as dyslipidemia and arterial hypertension fail to fully explain this phenomenon. Vascular function is impaired in those patients since arteriosclerotic processes such as osteoblastic transition (OT) and subsequent vascular mineralization (VM) are accelerated in chronic dialysis. OT and VM are predominantly located in vascular smooth muscle cells (VSMCs) of the arterial tunica media and are triggered by uremic toxins, which are elevated in ESRD-patients. Aim of this study was to assess molecular pathomechanisms of OT and VM in VSMCs to identify potential treatment-options. Methods Uremic sera from 14 patients with ESRD recruited within the “Permeability Enhancement to Reduce Chronic Inflammation” (PERCI-I)-trial at the dialysis centre of Charité-Universitätsmedizin Berlin, were compared to sera from healthy controls regarding proinflammatory biomarkers tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6) by ELISA. Genetic studies of the IL-6 promotor with promotor-deletion-assays and Electro-Mobility-Shift-Assays together with experiments with pharmacological inhibitors to characterize signaling pathways in VSMCs with pooled uremic and control sera of TNF-α were conducted. In addition, gene expression studies with markers for OT and determination of alkaline phosphatase as well as calcification assays were performed to study VSMC-mineralization. Results When compared with healthy controls, predialytic sera showed significantly increased levels of TNF-α and IL-6. Importantly, VSMCs demonstrated a TNF-α-mediated IL-6-induction in response to uremic sera, which was dependent on the Extracellular-signal-Regulated-Kinase-1 (ERK-1) and the Activator-Protein-1 (AP-1)/c-FOS complex transcription factor binding to the IL-6-promotor. In vitro, TNF-α and IL-6 strongly induced calcification of VSMCs and pharmacological inhibition of TNF-α, IL-6, ERK-1 and AP-1/cFOS reduced OT, mineralization and improved cell-survival. Conclusion Uremia in ESRD is characterized by a state of chronic inflammation with systemically elevated levels of TNF-α and IL-6. This is the first study to elucidate underlying pathomechanisms of OT and VM in humans identifying TNF-α-induced IL-6-production as an important new factor. This process could be further characterized by signaling via ERK-1 and AP-1/cFOS. Personalized pharmacological inhibition of TNF-α and IL-6 in patients with ESRD appears to be promising to reduce OT and VM and improve cardio-vascular-outcomes in those patients. Therefore, clinical studies should be encouraged to assess TNF-α-, and IL-6-inhibition as well as the use of dialysis membranes with improved clearance of uremic toxins.

Aim: We studied genetic epidemiology of primary large-joint (hip and knee) osteoarthritis (OA), in order to find disease risk factors by a candidate-gene approach. We used TNFA gene SNP rs1800629 in a case-control study in the Croatian Caucasian population. Method: We analyzed 225 hip and 205 knee OA patients (both with total joint replacements), and 554 healthy individuals, majority being blood donors. We genotyped for TNFA SNP rs1800629 (+308, C>T). Allelic and genotypic frequencies were compared between patients and controls. Results: The minor allele (T) of rs1800629 significantly conferred susceptibility only to hip OA (p < 5*10-5, OR = 1.81, CI 95% = 1.34 - 2.44). The major (C) allele was significantly associated with the protection to hip (p < 5*10-5, OR = 0.63, CI 95% = 0.41 - 0.74), but not knee OA. Patients with the homozygous genotype C/C had significantly lower risk of developing hip OA (< 3*10-4, OR = 0.53, CI 95% = 0.38 - 0.76), but had no association with knee OA. The homozygosity of the minor allele (T/T) has been significantly associated with susceptibility to only hip OA (< 2*10-2, OR = 2.56, CI 95% = 1.09 - 5.57). Conclusion. Our findings demonstrate that major and minor alleles of the rs1800629 are associated with lower or higher risk, respectively, to developing hip, but not knee OA in the Croatian population. The data suggest a difference in the etiology of hip OA from that of the knee, perhaps due to an unknown dissimilarity in vulnerability of these joints to the actions of TNFA. Alternatively, other genetic factors including long non-protein coding LOC100287329 and/or miR6832 in vicinity of rs1800629 might be involved in the observed risk. Keywords: Genetic Risk; TNFA; Osteoarthritis; Hip; SNP

Background: Single nucleotide polymorphism (SNP) within tumor necrosis factor alpha (TNF-α) gene promoter (−308G/A TNFA) is associated with higher gene expression. The role of this SNP as a risk factor for spontaneous preterm birth has been assessed in some regions and the findings were significantly different between race and ethnic groups. Aim: To provide the scientific evidence whether allele A within SNP −308G/A TNFA promoter is a risk factor for spontaneous preterm birth among Acehnese ethnic or not. Subjects and methods: In this case–control study, the genotypes of SNP −308G/A TNFA among 40 patients with spontaneous preterm birth and 40 patients with term birth were determined by real-time polymerase chain reaction (RT-PCR). The concentrations of TNF-α from blood were measured by enzyme-linked immunosorbent assay (ELISA). The differences in genotype distributions, dominant and recessive models, and allele frequencies between case and control groups were analyzed with Chi-squared test. Deviation of genotype frequencies from the Hardy–Weinberg equilibrium (HWE) was assessed by Fisher’s exact test. Results: This study found that the concentration of TNF-α between preterm and control groups was not statistically different, 5.5 ± 2.9 mg/dL vs. 10.1 ± 17.9 mg/dL, p = 0.112. The level of TNF-α had no strong association with either genotype distribution or allele frequency of SNP −308G/A TNFA. Furthermore, there was no association between mutant genotypes and spontaneous preterm birth (OR: 0.32; 95%CI: 0.08–1.33, p = 0.096) and between mutant allele and spontaneous preterm birth (OR: 0.35; 95%CI: 0.09–1.37, p = 0.105). Conclusion: SNP −308G/A TNFA is not associated with spontaneous preterm birth in Acehnese ethnic group.

Currently, there is a worldwide increase of patients with type 2 diabetes (T2D). During the progression of healthy obese to T2D status, there is an influx of immune cells, in particular macrophages, into visceral adipose tissue, accompanied by an increase of inflammatory cytokines, such as, IL6, TNFα and Hp. To get a better insight in the underlying mechanisms, we performed a quantitative LCMS analysis on a modified in vitro assay, combining 3T3L1 adipocytes and activated RAW264.7 macrophages, thus mimicking inflamed adipose tissue. Clinically known proteins, e.g. IL6, TNFα, AdipoQ, complement factor C3, B and D were identified, thus confirming the assay. In addition, we found 54 new proteins that can potentially be used for research into the mechanism of T2D. Comparison of our results to a study on human visceral fat of obese non-diabetic and obese diabetic subjects, indicated that AUH, NAGK, pCYT2, NNMT, STK39 and CSNK2A2 might indeed be linked to insulin resistance in humans. Moreover, the expression of some of these genes was also altered in human blood samples at early or later stages of insulin desensitization. Overall, we conclude that the direct contact co-culture of 3T3L1 adipocytes with activated macrophages could be a mechanistically relevant and partially translational model of inflamed visceral adipose tissue.

Gestational diabetes mellitus (GDM) is a unique form of glucose intolerance, in that it is transient and solely occurs in pregnancy. Pregnancies with GDM are at high risk of developing preeclampsia (PE), a leading cause of fetal and maternal morbidity or mortality. Since PE is associated with excessive activation of circulatory neutrophils and occurrence of neutrophil extracellular traps (NETs) in affected placentae, we examined these features in cases with GDM, as this could be a feature linking the two conditions. Our data indicate that neutrophil activity is indeed altered in GDM, exhibiting pronounced activation and spontaneous generation of NETs by isolated neutrophils in in vitro culture. In this manner, GDM may similarly affect neutrophil behavior and NET formation as witnessed in other forms of diabetes, with the addition of the physiological changes mediated by pregnancy. Since circulatory TNF-α levels are elevated in cases with GDM, a feature also observed in this study, we examined whether this pro-inflammatory cytokine contributed to neutrophil activation. By using infliximab, a clinically utilized TNF-α antagonist, we observed that the pro-NETotic effect of GDM sera was significantly reduced. We also detected pronounced neutrophil infiltrates in placentae from GDM cases. The occurrence of NETs in these tissues is suggested by the extracellular co-localization of citrullinated histones and myeloperoxidase. In addition, elevated neutrophil elastase (NE) mRNA and active enzymatic protein were also detected in such placentae. This latter finding could be important in the context of previous studies in cancer or diabetes model systems, which indicated that NE liberated from infiltrating neutrophils enters surrounding cells, altering cell signaling by the degradation of IRS1. These findings could potentiate the underlying inflammatory response process in GDM and possibly open an avenue for the therapeutic interventions in gestational hyperglycemia.

Проведено исследование ассоциации полиморфных локусов генов TNFa (rs1800629) и IL-1b (rs16944) с тяжестью течения атеросклеротического процесса. Изучалось распределение диких аллелей -308-A гена TNFa и -511-T гена IL-1b в группах пациентов с коронарным и периферическим атеросклерозом, разделенных по данным ангиографии и клиническим проявлениям. Установлено, что наличие -308-A аллеля гена TNFa значимо ассоциируется с более легким течением заболевания, а также более редким развитием инфаркта миокарда. Полиморфизм гена IL-1b (rs16944) не ассоциировался ни с одним из изучаемых параметров. Результаты исследования предполагают наличие протективной роли -308-A аллеля гена TNFa в развитии тяжелого течения атеросклероза., The purpose of the study was to investigate association of TNFa (rs1800629) and IL-1b (rs16944) gene polymorphisms with severity of atherosclerotic process. We studied distribution of -308-A TNFa and -511-T IL-1b wild alleles in patients with coronary and peripheral atherosclerosis, divided into groups by angiographic and clinical data. It was found that presence of TNFa -308-A allele was significantly associated with milder disease, as well as rare myocardial infarction. IL-1b rs16944 polymorphism has not shown any association with parameters presented. The study results suggest a protective role for TNFa -308-A allele against severe courses of atherosclerosis.

В настоящее время активно дискутируется вопрос об андрогенном дефиците как об одном из основных патогенетических факторов формирования нарушений углеводного обмена у мужчин, активно изучается роль нарушений состояния адаптивного иммунитета в патогенезе метаболических заболеваний и их сосудистых осложнений. Цель исследования оценить влияние андрогенного дефицита на формирование нарушений углеводного обмена у мужчин с ожирением. Материал и методы. Обследованы 120 мужчин с ожирением в возрасте 29-66 лет, считающих себя здоровыми. Пациенты разделены на 2 группы: 1-ю составили 56 человек с нормальным уровнем общего тестостерона (T), 2-ю 64 человека с уровнем общего тестостерона (T), Androgen deficiency is actively discussed as one of the main pathogenetic factors in the formation of violations of carbohydrate metabolism in men, as well as the role of disorders of the adaptive immunity in the pathogenesis of metabolic diseases and their vascular complications Objective. To assess the effect of androgen deficiency and imbalance of the immune system on the formation of violations of carbohydrate metabolism in obese men. Materials and metods. There were examine 120 men with obesity aged 29-66 years, who consider themselves healthy, were examined. Patients are divided into two groups: the first consisted of 56 people with a normal level of total testosterone (T), the second 64 people with a total T level of less than 12.1 mmol/l. In each of the main groups, subgroups are distinguished depending on the state of carbohydrate metabolism: 1a subgroup obese patients without carbohydrate metabolism disorder, 1b subgroup with obesity and carbohydrate metabolism disorder, 2a subgroup with obesity and androgen deficiency and 2b subgroup with obesity, carbohydrate metabolism disorder and androgen deficiency. The key indicators of carbohydrate, lipid, purine metabolism, and the level of sex hormones were studied. The main characteristics of adaptive immunity (С03+, С04+, С08+, С016+, С025+) and the level of secretion of pro-inflammatory cytokines TNFa and IL-6 were evaluated. The control group consisted of 25 healthy men with normal body weight. Results. Analysis of the metabolic and immune status of obese patients revealed an increase in total cholesterol, triglycerides, ALT, an increase in the insulin resistance marker HOMA-IR, a decrease in the level of 25-OH vitamin D, an increase in CRP, and a decrease in СD4+-lymphocytes, cytotoxic СDl6+-lymphocytes in comparison with the control group. At the same time, the greatest changes were detected in a subgroup of patients with a deficiency of testosterone and carbohydrate metabolism disorder. In addition, these patients showed a marked imbalance in the content of the main pro-inflammatory cytokines TNFa and IL-6. Conclusion. Visceral obesity in men is a factor of high risk of metabolic disorders and androgen deficiency in men. The current androgen deficiency leads to the formation of more severe metabolic and immunological changes in obese patients. Nonspecific systemic inflammation, activation of the cytotoxic link of immunity, hyperproduction of proinflammatory cytokines can be considered as a modifying factor of the progression of the initial carbohydrate metabolism disorder before the development of the manifest form of type 2 diabetes.

A pathogenic link between erectile dysfunction (ED) and metabolic syndrome (MetS) is now well established. Nonalcoholic steatohepatitis (NASH), the hepatic hallmark of MetS, is regarded as an active player in the pathogenesis of MetS-associated cardiovascular disease (CVD). This study was aimed at evaluating the relationship between MetS-induced NASH and penile dysfunction. We used a non-genomic, high fat diet (HFD)-induced, rabbit model of MetS, and treated HFD rabbits with testosterone (T), with the selective farnesoid X receptor (FXR) agonist obeticholic acid (OCA), or with the anti-TNFα mAb infliximab. Rabbits fed a regular diet were used as controls. Liver histomorphological and gene expression analysis demonstrated NASH in HFD rabbits. Several genes related to inflammation (including TNFα), activation of stellate cells, fibrosis, and lipid metabolism parameters were negatively associated to maximal acetylcholine (Ach)-induced relaxation in penis. When all these putative liver determinants of penile Ach responsiveness were tested as covariates in a multivariate model, only the association between hepatic TNFα expression and Ach response was confirmed. Accordingly, circulating levels of TNFα were increased 15-fold in HFD rabbits. T and OCA dosing in HFD rabbits both reduced TNFα liver expression and plasma levels, with a parallel increase of penile eNOS expression and responsiveness to Ach. Also neutralization of TNFα with infliximab treatment fully normalized HFD-induced hypo-responsiveness to Ach, as well as responsiveness to vardenafil, a phosphodiesterase type 5 inhibitor. Thus, MetS-induced NASH in HFD rabbits plays an active role in the pathogenesis of ED, likely through TNFα, as indicated by treatments reducing liver and circulating TNFα levels (T or OCA), or neutralizing TNFα action (infliximab), which significantly improve penile responsiveness to Ach in HFD rabbits.

Fragestellung: Die frühe inflammatorische Phase spielt eine wichtige Rolle bei der Geweberegeneration. Welchen Einfluss diese Prozesse auf Heilung bzw. Degeneration der Sehne haben, ist bis jetzt noch unzureichend geklärt. Ziel der Studie war es, den Effekt einer inflammatorischen Umgebung[zum vollständigen Text gelangen Sie über die oben angegebene URL], Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2016)

Myelodysplastic syndrome (MDS) is characterized by an ineffective hematopoiesis with production of aberrant clones and a high cell apoptosis rate in bone marrow (BM). Macrophages are in charge of phagocytosis. Innate Immune cells and specific T cells are in charge of immunosurveillance. Little is known on BM cell recruitment and activity as BM aspirate is frequently contaminated with peripheral blood. But evidences suggest an active role of immune cells in protection against MDS and secondary leukemia. BM CD8(+) CD28(-) CD57(+) T cells are directly cytotoxic and have a distinct cytokine signature in MDS, producing TNF-α, IL-6, CCL3, CCL4, IL-1RA, TNFα, FAS-L, TRAIL, and so on. These tools promote apoptosis of aberrant cells. On the other hand, they also increase MDS-related cytopenia and myelofibrosis together with TGFβ. IL-32 produced by stromal cells amplifies NK cytotoxicity but also the vicious circle of TNFα production. Myeloid-derived suppressing cells (MDSC) are increased in MDS and have ambiguous role in protection/progression of the diseases. CD33 is expressed on hematopoietic stem cells on MDS and might be a potential target for biotherapy. MDS also has impact on immunity and can favor chronic inflammation and emergence of autoimmune disorders. BM is the site of hematopoiesis and thus contains a complex population of cells at different stages of differentiation from stem cells and early engaged precursors up to almost mature cells of each lineage including erythrocytes, megakaryocytes, myelo-monocytic cells (monocyte/macrophage and granulocytes), NK cells, and B cells. Monocytes and B cell finalize their maturation in peripheral tissues or lymph nodes after migration through the blood. On the other hand, T cells develop in thymus and are present in BM only as mature cells, just like other well vascularized tissues. BM precursors have a strong proliferative capacity, which is usually associated with a high risk for genetic errors, cell dysfunction, and consequent cell death. Abnormal cells are prone to destruction through spontaneous apoptosis or because of the immunosurveillance that needs to stay highly vigilant. High rates of proliferation or differentiation failures lead to a high rate of cell death and massive release of debris to be captured and destroyed (1). Numerous macrophages reside in BM in charge of home-keeping. They have a high capacity of phagocytosis required for clearing all these debris.

Mutations in MECP2 cause Rett syndrome, a severe neurological disorder with autism-like features. Duplication of MECP2 also causes severe neuropathology. Both diseases display immunological abnormalities that suggest a role for MECP2 in controlling immune and inflammatory responses. Here, we used mecp2-null zebrafish to study the potential function of Mecp2 as an immunological regulator. Mecp2 deficiency resulted in an increase in neutrophil infiltration and upregulated expression of the pro- and anti-inflammatory cytokines Il1b and Il10 as a secondary response to disturbances in tissue homeostasis. By contrast, expression of the proinflammatory cytokine tumor necrosis factor alpha (Tnfa) was consistently downregulated in mecp2-null animals during development, representing the earliest developmental phenotype described for MECP2 deficiency to date. Expression of tnfa was unresponsive to inflammatory stimulation, and was partially restored by re-expression of functional mecp2. Thus, Mecp2 is required for tnfa expression during zebrafish development and inflammation. Finally, RNA sequencing of mecp2-null embryos revealed dysregulated processes predictive for Rett syndrome phenotypes., Summary: As shown by evaluating the levels of pro- and anti-inflammatory cytokines in mecp2-null zebrafish, Mecp2 is required for tnfa expression during zebrafish development and inflammation.

Работа посвящена оценке ассоциаций однонуклеотидных полиморфизмов (ОНП) Pro12Ala гена PPARγ и -308G/A гена TNFα с риском абдоминального ожирения среди женщин репродуктивного возраста. В ходе проведения работы были изучены данные литературы о причинах, этиологии и патогенезе абдоминального ожирения, проведен скрининг ОНП Pro12Ala PPARγ и -308G/A TNFα в группе женщин репродуктивного возраста с избыточным весом и абдоминальным ожирением и в группе женщин репродуктивного возраста с нормальной массой тела (контроль). Сопоставлены частоты генотипов по ОНП Pro12Ala гена PPARγ и по ОНП -308G/A гена TNFα в группе женщин с избыточным весом и абдоминальным ожирением и в группе женщин с нормальной массой. Оценено влияние вариантов ОНП Pro12Ala гена PPARγ и -308G/A гена TNFα на антропометрические и клинические показатели, а также на уровень экспрессии генов PPARγ и TNFα в интраабдоминальной жировой ткани в исследуемых группах., Work is devoted to assessing the association of single nucleotide polymorphisms (SNPs) Pro12Ala PPARγ gene and -308G/A TNFa gene with risk of abdominal obesity among women of reproductive age. During the the work were examined literature data on the causes, etiology and pathogenesis of of abdominal obesity, screened SNPs Pro12Ala PPARγ and -308G/A TNFα in the group of women of childbearing age are overweight and abdominal obesity in a group of women of reproductive age with normal body weight were studied ( control). We compared the frequency of genotypes at SNPs Pro12Ala PPARγ gene and SNPs -308G/A TNFα gene in the group of women with overweight and abdominal obesity in a group of women with normal weight. We were examined effect of SNP variants of the Pro12Ala PPARγ gene and -308G/A TNFα gene on anthropometric and clinical indicators, and on the level of the PPARγ and TNFα gene expression in intraabdominal adipose tissue in the test groups.

none 14 si Biorecognition is a central event in biological processes in the living systems that is also widely exploited in technological and health applications. We demonstrate that the Electrolyte Gated Organic Field Effect Transistor (EGOFET) is an ultrasensitive and specific device that allows us to quantitatively assess the thermodynamics of biomolecular recognition between a human antibody and its antigen, namely, the inflammatory cytokine TNFα at the solid/liquid interface. The EGOFET biosensor exhibits a superexponential response at TNFα concentration below 1 nM with a minimum detection level of 100 pM. The sensitivity of the device depends on the analyte concentration, reaching a maximum in the range of clinically relevant TNFα concentrations when the EGOFET is operated in the subthreshold regime. At concentrations greater than 1 nM the response scales linearly with the concentration. The sensitivity and the dynamic range are both modulated by the gate voltage. These results are explained by establishing the correlation between the sensitivity and the density of states (DOS) of the organic semiconductor. Then, the superexponential response arises from the energy-dependence of the tail of the DOS of the HOMO level. From the gate voltage-dependent response, we extract the binding constant, as well as the changes of the surface charge and the effective capacitance accompanying biorecognition at the electrode surface. Finally, we demonstrate the detection of TNFα in human-plasma derived samples as an example for point-of-care application. Berto, Marcello; Casalini, Stefano; Di Lauro, Michele; Marasso, Simone L; Cocuzza, Matteo; Perrone, Denis; Pinti, Marcello; Cossarizza, Andrea; Pirri, Candido F; Simon, Daniel T; Berggren, Magnus; Zerbetto, Francesco; Bortolotti, Carlo A; Biscarini, Fabio Berto, Marcello; Casalini, Stefano; Di Lauro, Michele; Marasso, Simone L; Cocuzza, Matteo; Perrone, Denis; Pinti, Marcello; Cossarizza, Andrea; Pirri, Candido F; Simon, Daniel T; Berggren, Magnus; Zerbetto, Francesco; Bortolotti, Carlo A; Biscarini, Fabio

WOS: 000286779300025, PubMed: 20005085, It has been shown that coal dust exposure stimulates inflammatory response leading to increased release of cytokines from monocytes such as TNF-alpha and IL1 These released cytokines play the key role in the pathogenesis of pneumoconiosis including coal workers' pneumoconiosis. In this study, we investigated TNFA, IL1A, IL1B and IL1RA genes variations on basal, lipopolysaccharide and coal dust-induced cytokine release from blood monocytes of homozygous allele and minor variant allele carriers in Turkish coal workers and CWP patients. According to the genotyping results, TNFA -238 gene polymorphism was found as a risk factor in CWP development (OR=3.79) and to in vitro results; release of both TNF-alpha and IL1 cytokines from the monocytes in CWP patients was significantly increased compared to the healthy workers. Also. LPS and coal dust stimulated release of TNF-alpha, which was significantly higher in allele 2 carriers compared to subjects carrying allele 1 in both the groups. These data suggest that the coal dust-induced release of TNF-alpha from monocytes may be a useful biomarker of CWP. (C) 2009 Elsevier GmbH. All rights reserved., Ankara UniversityAnkara University [20030803036], This study was supported by Research Fund of Ankara University (20030803036).

Several HIV-1 infected patients show bone loss and osteopenia/osteoporosis during the course of disease. The mechanisms underlying this degenerative process are largely unsettled and it has not been determined yet whether bone dysfunction is linked to HIV-1-mediated direct and/or indirect effects on osteoblasts/osteoclasts cross-talk regulation. This study investigated the effects of HIV-1(IIIb) and HIV-1(ADA) strains on osteoblasts using the osteoblast-derived cell line (HOBIT) and primary human osteoblasts as cellular models. The challenge of these cell cultures by both HIV-1 strains triggered a significant apoptosis activation unrelated to viral infection, since proviral HIV-1 DNA and supernatant HIV-1 RNA were not detected by real time PCR or b-DNA assays respectively. Under the experimental conditions, even heat-inactivated HIV-1 or cross-linked recombinant gp120 treatment of HOBIT and osteoblasts induced programmed cell death, suggesting that apoptosis is regulated by the interaction between HIV-1 gp120 and cell membrane. The analysis of cell culture supernatants showed a significant up-regulation of TNFalpha, a pleiotropic protein considered an apoptosis inducer in the osteoblast model. In fact, pretreatment of HOBIT and osteoblast cell cultures with anti-TNFalpha polyclonal antibody tackled effectively HIV-1 related induction of cell apoptosis. As a whole, these results indicate that HIV-1 may impair bone mass structure homeostasis by TNFalpha regulated osteoblast apoptosis.

La retinosis pigmentaria (RP) es una forma de degeneración retiniana hereditaria caracterizada por la pérdida de los fotorreceptores (bastones y conos) de la retina. Constituye la principal causa genética de ceguera en los países desarrollados. Debido a su elevada heterogeneidad genética es difícil comprender los mecanismos patogenéticos responsables de la muerte de los fotorreceptores. Las mutaciones genéticas son las responsables de la apoptosis de los bastones. Sin embargo, la muerte de los conos parece debida a los cambios metabólicos que provoca la degeneración de los bastones como la hiperoxia (estrés oxidativo y nitrosativo), la secreción de diversos factores (citoquinas, quimioquinas) por parte de los bastones y otras células del entorno, etc. La muerte de los conos provoca la pérdida de la visión central en RP. El objetivo principal de este proyecto es evaluar el papel de la inflamación en pacientes con retinosis pigmentaria y en un modelo experimental, el ratón rd10. En concreto se determinará la presencia de factores inflamatorios en pacientes con RP y el efecto de la inhibición de la citoquina proinflamatoria, TNF¿, sobre la progresión de la enfermedad en el ratón rd10 y un modelo porcino ex vivo de degeneración retiniana. La caracterización y validación de este modelo ex vivo podría ser una alternativa útil para la comprensión de los mecanismos moleculares implicados en la muerte de los fotorreceptores en enfermedades retinianas. La inhibición del TNF¿ con anticuerpos específicos podría reducir el proceso inflamatorio y con ello, la muerte de los fotorreceptores en ratones rd10. Esto supondría el establecimiento de una nueva diana terapéutica para el desarrollo de tratamientos que previniesen o retrasasen el avance de la enfermedad en humanos., Martínez Fernández De La Cámara, CI. (2015). Papel del estrés oxidativo y la inflamación en la retinosis pigmentaria. Efecto de la inhibición del TNFA en la progresión de la degeneración retiniana [Tesis doctoral no publicada]. Universitat Politècnica de València. doi:10.4995/Thesis/10251/48803., TESIS

Vascular and metabolic effects of selective PDE-5 inhibition Clinical and experimental studies Lovisa Sjögren Department of Molecular and Clinical Medicine, Institute of Medicine at Sahlgrenska Academy, University of Gothenburg Key words: Type 2 diabetes, phosphodiesterase-5 inhibition, inflammation, endothelial cells, HUVEC. TNFα, ICAM-1, VCAM-1, E-Selectin, JNK, MAPK Background: Type 2 diabetes (T2D) patients show impaired glucose metabolism, endothelial dysfunction, chronic low-grade inflammation as well as an increased risk of cardiovascular disease. Phosphodiesterase-5 (PDE-5) inhibition amplifies nitric oxide (NO) signaling within the cell and has emerged as a novel treatment option against microvascular insulin resistance and subclinical inflammation. However, very little is known about metabolic effects induced by PDE-5 inhibition in T2D patients. The overall aim of this thesis was to investigate whether the selective PDE-5 inhibitor tadalafil demonstrate any positive effect on glucose uptake, vascular function and inflammatory markers in T2D patients, and whether any molecular mechanism could be linked to the tadalafil effect in cultured endothelial cells (HUVEC). Methods and results Paper I-III Paper I: 17 female T2D patients and healthy controls were recruited and investigated with muscle microdialysis, plethysmography and sampling from an artery and a deep vein in the forearm, to study acute effects of 20 mg tadalafil compared with placebo in a double-blind, randomized controlled trial (RCT). We found that tadalafil treatment resulted in increased capillary recruitment and glucose uptake in forearm muscle. Paper II: Twenty-six T2D patients of both gender were included in a RCT with parallel groups. Tadalafil 20 mg or placebo were administered before a mixed meal and participants were investigated with muscle microdialysis, plethysmography and blood sampling from an artery and a deep vein in the forearm. In a post hoc analysis we showed positive microvascular, macrovascular and metabolic effects and decreased circulating levels of the vasoconstricting peptide endothelin-1. Paper III: We studied the effect of tadalafil on inflammatory signaling in HUVEC using Western blot, ELISA and RT-PCR. The results showed that tadalafil reduced gene expression of inflammatory markers and reduced secretion of endothelin-1. Moreover, tadalafil attenuated TNFα-induced phosphorylation of c-Jun N-terminal Kinase (JNK). Conclusions: Acute administration of the PDE-5 inhibitor tadalafil induced positive metabolic and vascular effects in T2D patients. Furthermore, tadalafil reduced expression of endothelin-1 via a mechanism involving JNK.

Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, Universidade de Lisboa, Faculdade de Farmácia, 2015 Made available in DSpace on 2017-03-07T11:01:13Z (GMT). No. of bitstreams: 3 MICF_Carolina_Trincao.pdf: 1207260 bytes, checksum: a6f4f0bc150e969c8c6c449471e6a021 (MD5) license.txt: 1195 bytes, checksum: 25733b0b84e8845b1d09ead22e7c5a2c (MD5) MICF_Carolina_Trincao.pdf: 1207260 bytes, checksum: a6f4f0bc150e969c8c6c449471e6a021 (MD5) Previous issue date: 2015

Contains fulltext : 153756.pdf (Publisher’s version ) (Open Access) The effect of the anti-inflammatory cytokine interleukin-37 (IL-37) on host defense against Candida infections remains unknown. We assessed the role of IL-37 in a murine model of disseminated candidiasis using mice transgenic for human IL-37 (hIL-37Tg). Upon exposure to Candida albicans pseudohyphae, macrophages from hIL-37Tg mice release 39% less TNFalpha compared to cells from wild-type (WT) mice (p = 0.01). In vivo, hIL-37Tg mice displayed a decreased capacity to recruit neutrophils to the site of infection. These defects were associated with increased mortality and organ fungal growth in hIL-37Tg compared to WT mice. We conclude that IL-37 interferes with the innate protective anti-Candida host response by reducing the production of proinflammatory cytokines and suppressing neutrophil recruitment in response to Candida, resulting in an increased susceptibility to disseminated candidiasis.

Introduction: our objective was to investigate the effects of the administration of pancreatic homogenates, with or without enzymatic activation, to healthy animals regarding cytokine serum levels and the development of pulmonary distress. Material and methods: 106 male Wistar rats, divided into three groups, were studied: group A, intraperitoneal administration of homogenates activated with enterokinase; group B, homogenates without enterokinase; and group C, control group with administration of physiological saline solution. Each group was divided into 4 subgroups according to the time of sacrifice: 0, 2, 6 and 24 hours. We studied the pulmonary and pancreatic histology, serum parameters of renal and hepatic function, and serum levels of IL-1ß, IL-6 and TNFa. Results: there was no mortality in any group. Pancreatic disorders in A and B groups were noted at 24 hours. These two groups had statistically significant higher transaminase serum levels than those of the control group, as well as statistically significant higher creatinine levels in group A. IL-1ß showed a statistically significant higher level at 6 h in both groups, A and B, but was higher in group A, which also exhibited significant pulmonary histologic damage with respect to controls at 6 h. Conclusions: the higher IL-1ß level in group A may result from production by peritoneal macrophages under the influence of homogenate enzymatic activation. This may be the reason for lung damage.Introducción: nuestro objetivo es investigar, en animales sanos, los efectos de la administración de homogeneizado pancreático, con y sin activación enzimática, sobre los niveles séricos de citoquinas y el desarrollo de lesiones pulmonares. Material y métodos: se estudiaron 106 ratas Wistar macho divididas en 3 grupos: A: administración intraperitoneal de homogeneizado pancreático activado con enteroquinasa; B: homogeneizado sin enteroquinasa; y C: control, con la administración de suero fisiológico. Cada grupo fue dividido en 4 subgrupos de acuerdo al tiempo de sacrificio: 0, 2, 6 y 24 horas. Estudiamos la histología pancreática y pulmonar, parámetros séricos de función renal, hepática y los niveles séricos de IL-1ß, IL-6 y TNFa. Resultados: no hubo mortalidad en ningún grupo. Se observaron alteraciones pancreáticas en los grupos A y B a las 24 horas. Estos dos grupos presentaron niveles de transaminasas significativamente más elevados que aquellos del grupo control. Los niveles séricos de creatinina estaban más elevados en el grupo A. Los valores de IL-1ß fueron significativamente más altos a las 6 horas en ambos grupos A y B, aunque mayor en el grupo A, el cual también presentó más lesiones histológicas pulmonares en relación con los controles a las 6 horas. Conclusiones: los niveles de IL-1ß más elevados en el grupo A podrían deberse a la activación enzimática del homogeneizado que podría inducir la producción de esta citoquina por los macrófagos peritoneales, lo que a su vez podría ser el promotor de las lesiones pulmonares.