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The management of metastatic renal cell carcinoma (mRCC) continues to be a therapeutic challenge; however, the options for systemic therapy in this setting have exploded over the past 20 years. From the advent of toxic cytokine therapy to the subsequent discovery of targeted therapy (TT) and immune checkpoint inhibitors, the landscape of viable treatment options continues to progress. With the arrival of cytokine therapy, two randomized trials demonstrated a survival benefit for upfront cytoreductive nephrectomy (CN) plus interferon therapy and this approach became the standard for surgical candidates. However, it was difficult to establish the role and the timing of CN with the subsequent advent of TT, just a few years later. More recently, two randomized phase III studies completed in the TT era questioned the use of CN and brought to light the role of risk stratification while selecting patients for CN. Careful identification of the mRCC patients who are likely to have a rapid progression of the disease is essential, as these patients need prompt systemic therapy. With the continued advancement of systemic therapy using the immune checkpoint inhibitors as a first line therapy, the role of CN will continue to evolve. [ABSTRACT FROM AUTHOR]

The current challenge of the COVID-19 pandemic is complicated by the limited therapeutic options against the virus, with many being anecdotal or still undergoing confirmatory trials, underlining the urgent need for novel strategies targeting the virus. The pulmotropic virus causes loss of oxygenation in severe cases with acute respiratory distress syndrome (ARDS) and need for mechanical ventilation. This work seeks to introduce placental extract-derived biologically active components as a therapeutic option and highlights their mechanism of action relevant to COVID-19 virus. Human placenta has been used in clinical practice for over a century and there is substantial experience in clinical applications of placental extract for different indications. Aqueous extract of human placentacontains growth factors, cytokines/chemokines, natural metabolic and other compounds, anti-oxidants, amino acids, vitamins, trace elements and biomolecules, which individually or in combination show accelerated cellular metabolism, immunomodulatory and anti-inflammatory effects, cellular proliferation and stimulation of tissue regeneration processes. Placental extract treatment is proposed as a suitable therapeutic approach consideringthe above properties which could protect against initial viral entry and acute inflammation of alveolar epithelial cells, reconstitute pulmonary microenvironment and regenerate the lung. We reviewed useful therapeutic information of placental biomolecules in relation to COVID-19 treatment. We propose the new approach of using placental growth factors, chemokines and cytokine which will execute antiviral activity in coordination with innate and humoral immunity and improve patient's immunological responses to COVID-19. Executing a clinical trial using placental extract as preventive, protective and/or therapeutic approach for COVID-19treatment could advance the development of a most promising therapeutic candidate that can join the armamentaria against the COVID-19 virus. [ABSTRACT FROM AUTHOR]

Objective To discuss the current knowledge on the impact of commonly used biologic agents (i.e. anti–tumor necrosis factor–alpha [anti-TNF-α] and anti–nerve growth factor [anti-NGF]) in the management of low back pain with or without sciatica. Methods A narrative literature review of studies investigating the use of biologic agents for the management of low back pain and sciatica was conducted. We searched MEDLINE and EMBASE for English language publications. A hand-search of reference lists of relevant studies was also performed. Results Although some observational studies showed that inhibition of TNF-α reduced pain and improved function, randomized controlled trials and a meta-analysis failed to demonstrate the superiority of anti-TNF-α over placebo in this regard. Anti-TNF-α, however, reduced the risk of having invasive procedures such as discectomy and radicular block in cases of sciatica. Conversely, controlled studies showed moderate pain reduction and mild functional improvement with anti-NGF administration, but the side effect profile of anti-NGF was unfavorable compared with placebo. Conclusions Overall, anticytokine treatments have limited efficacy in patients with chronic low back pain with or without sciatica. However, larger and better-designed studies may need to be performed in specific patient subpopulations. Low back pain is particularly disabling in younger patients. This group therefore represents a potential target population for investigating the effectiveness of anticytokine therapies, especially where other pharmacological and nonpharmacological management strategies have failed. [ABSTRACT FROM AUTHOR]

Abstract Melatonin has important immuno-regulatory effects in inflammatory disorders but its specific role in Helicobacter pylori induced gastritis remains unclear. The aim of our study was to analyze the activity of melatonin against H. pylori induced gastritis in vivo, and explore the underlying mechanisms. The H. pylori infected mice showed extensive inflammatory cell infiltration in the gastric mucosa and submucosa, along with significantly reduced spleen and thymus weight. However, 2 and 6 weeks of treatment with 25 and 50 mg/kg melatonin restored the thymus weights relative to that of the untreated mice. TLR2 was upregulated in the gastric mucosa of the infected mice, which was restored to normal levels after 2 and 6 weeks of melatonin treatment. In contrast, TLR4 levels were similar between the treated and untreated mice. Furthermore, melatonin treatment restored spleen Foxp3 and serum TGF-β1 levels that were respectively increased and decreased in the infected mice. H. pylori infected mice also showed a decrease in the serum levels of IL-2, IL-6, IL-10, IL-17, IFN-γ and TFN-α following 2 and 6 weeks of melatonin treatment compared to the untreated mice. Melatonin treatment also resulted in decreased CD4+CD25+Foxp3+ Treg cell count in the spleen. The expression of TLR2, MyD88, p-ERK, p-p38, p65, p50 and Foxp3 in the gastric tissues were lower in the untreated mice compared to mice treated with melatonin for 2 weeks. However, the expression levels evened out after 6 weeks of treatment. Taken together, melatonin alleviates H. pylori induced gastritis by regulating TGF-β1 and Foxp3 expression via the TLR2 and TLR4 pathways. Highlights • (1) We showed for the first time that the activity of melatonin against H. pylori induced gastritis; • (2) Melatonin decreased H. pylori infected mice Foxp3 and cytokines expression; • (3) Melatonin exert its immunomodulatory effect via the TLR2 or TLR4 pathway. [ABSTRACT FROM AUTHOR]

Stress-related changes in β-cell mRNA levels result from a balance between gene transcription and mRNA decay. The regulation of RNA decay pathways has not been investigated in pancreatic β-cells. We found that no-go and nonsense-mediated RNA decay pathway components (RDPCs) and exoribonuclease complexes were expressed in INS-1 cells and human islets. Pelo, Dcp2, Dis3L2, Upf2, and Smg1/5/6/7 were upregulated by inflammatory cytokines in INS-1 cells under conditions where central β-cell mRNAs were downregulated. These changes in RDPC mRNA or corresponding protein levels were largely confirmed in INS-1 cells and rat/human islets. Cytokine-induced upregulation of Pelo, Xrn1, Dis3L2, Upf2, and Smg1/6 was reduced by inducible nitric oxide synthase inhibition, as were endoplasmic reticulum (ER) stress, inhibition of Ins1/2 mRNA, and accumulated insulin secretion. Reactive oxygen species inhibition or iron chelation did not affect RDPC expression. Pelo or Xrn1 knockdown (KD) aggravated, whereas Smg6 KD ameliorated, cytokine-induced INS-1 cell death without affecting ER stress; both increased insulin biosynthesis and medium accumulation but not glucose-stimulated insulin secretion in cytokine-exposed INS-1 cells. In conclusion, RDPCs are regulated by inflammatory stress in β-cells. RDPC KD improved insulin biosynthesis, likely by preventing Ins1/2 mRNA clearance. Pelo/Xrn1 KD aggravated, but Smg6 KD ameliorated, cytokine-mediated β-cell death, possibly through prevention of proapoptotic and antiapoptotic mRNA degradation, respectively. [ABSTRACT FROM AUTHOR]

Introduction: Diabetic macular edema is a sight-threatening disease and a major cause for blindness for people in working age. The pathogenesis or pathophysiology of this condition is multifactorial and different pathways have been identified, such as inflammation, the modulation of vascular integrity and tractional forces at the vitreomacular interface. Considering the significance of these pathogenetic mechanisms as the main targets in the modern treatment of diabetic macular edema, the current review aims to provide a detailed insight in the current understanding regarding these pathways. Areas covered: This review discusses original research articles including basic science and clinical studies as well as review articles focusing on inflammation, the vascular endothelial growth factor (VEGF) pathway and the role of the vitreomacular interface. The literature was searched using Medline/PubMed and articles were selected given their relevance for the topic to be discussed. Expert commentary: In recent years, knowledge regarding the pathophysiology of diabetic macular edema has significantly increased. Several interacting pathways with multiple growth factors, cytokines, cellular responses and so on, have been identified. Some of these insights have been successfully transferred into current treatment strategies already, such as VEGF suppression or anti-inflammatory treatments using steroids. It will be a future challenge not only to further identify additional pathophysiological aspects, but also to better understand their interactions and relevance as potential treatment targets and potential combinations. [ABSTRACT FROM AUTHOR]

One strategy to control leishmaniasis is vaccination with potent antigens alongside suitable adjuvants. The use of toll-like receptor (TLR) agonists as adjuvants is a promising approach in Leishmania vaccine research. Leishmania (L.) tropica is among the less-investigated Leishmania species and a causative agent of cutaneous and sometimes visceral leishmaniasis with no approved vaccine against it. In the present study, we assessed the adjuvant effects of a TLR4 agonist, monophosphoryl lipid A (MPL) and a TLR7/8 agonist, R848 beside two different types of Leishmania vaccine candidates; namely, whole-cell soluble L. tropica antigen (SLA) and recombinant L. tropica stress-inducible protein-1 (LtSTI1). BALB/c mice were vaccinated three times by the antigens (SLA or LtSTI1) with MPL or R848 and then were challenged by L. tropica. Delayed-type hypersensitivity (DTH), parasite load, disease progression and cytokines (IL-10 and IFN-γ) responses were assessed. In general compared to SLA, application of LtSTI1 resulted in higher DTH, higher IFN-γ response and lower lymph node parasite load. Also compared to R848, MPL as an adjuvant resulted in higher DTH and lower lymph node parasite load. Although, no outstanding ability for SLA and R848 in evoking immune responses of BALB/c mice against L. tropica infection could be observed, our data suggest that LtSTI1 and MPL have a better potential to control L. tropica infection and could be pursued for the development of effective vaccination strategies. [ABSTRACT FROM AUTHOR]

Abstract: Background: Kawasaki disease shock syndrome (KDSS) is an uncommon presentation of Kawasaki disease (KD). KDSS has been associated with more severe markers of inflammation, coronary abnormalities and i.v. immunoglobulin (IVIG) resistance. Methods: A retrospective, descriptive study of children with KDSS in two hospitals was performed. Relevant articles about KD and shock were collected, and demographic data, clinical presentation, laboratory variables, echocardiogram findings, treatment and special features were analyzed when available. Twelve patients diagnosed with KDSS were retrospectively reviewed from two centers in Mexico, along with 91 additional cases from the literature. Results: Seventy‐two patients presented with complete KD (69.9%), and 30.1% (31/103) had unusual KD manifestations. The most frequent diagnosis at the time of admission was toxic shock syndrome (TSS; n = 20). Sixteen of the 20 had coronary artery abnormalities. Overall, abnormalities in the coronary arteries were documented in 65% of the patients. The mortality rate was 6.8%. Conclusion: The presence of coronary aneurysms was significantly and positively correlated with male gender, IVIG resistance, inotrope treatment, cardiac failure, abdominal pain and neurological symptoms. IVIG‐resistant patients had higher neutrophil : lymphocyte ratio. Abdominal symptoms, hypoalbuminemia and elevated C‐reactive protein were present in almost all of the patients. Multisystem involvement with atypical presentation in KDSS is frequent. An important differential diagnosis is TSS. Mechanical ventilation, gastrointestinal and neurological symptoms were associated with IVIG resistance and the presence of coronary aneurysms. The first line of treatment includes IVIG and pulse corticosteroids; in severe cases, infliximab, anakinra, cyclosporine or plasmapheresis are alternative treatment options. [ABSTRACT FROM AUTHOR]

It is well known that unmethylated 20-deoxycytidine-phosphate-20-guanine (CpG) sequences alone or in longer DNA and RNA oligonucleotides can act like pathogen-associated molecular patterns (PAMPs) and trigger the innate immune response leading to deleterious cytokine production via Toll-like receptors (TLRs). Clearly, such CpG or CpG-containing sequences in aptamers intended for therapy could present very damaging side effects to patients. Previous antisense oligonucleotide developers were faced with the same basic CpG dilemma and devised not only avoidance, but other effective strategies from which current aptamer developers can learn to ameliorate or eliminate damaging CpG effects. These strategies include obvious methylation of cytosines in the aptamer structure, as long as it does not affect aptamer binding in vivo, truncation of the aptamer to its essential binding site, backbone modifications, co-administration of antagonistic or suppressive oligonucleotides, or other novel drugs under development to lessen the toxic CpG effect on innate immunity. [ABSTRACT FROM AUTHOR]

Adult-onset Still’s disease (AOSD) is a rare inflammatory disorder of unknown etiology generally characterized by persistent high spiking fever, evanescent rash, and polyarthritis. The pathogenesis of AOSD is only partially known. The pivotal role of macrophage cell activation, which leads to T-helper 1 (Th1) cell cytokine activation, is now well-established in AOSD. Moreover, pro-inflammatory cytokines such as interleukin (IL)-1, -6, and -18 seem to play a key role in this disorder, giving rise to the development of new targeted therapies. For years, treatment of AOSD has been largely empirical, using nonsteroidal anti-inflammatory drugs, corticosteroids, and disease-modifying antirheumatic drugs. Patients with steroid- and methotrexate-refractory AOSD can now benefit from efficient and well-tolerated biologic agents such as IL-1, IL-6, and tumor necrosis factor-α antagonists. [ABSTRACT FROM AUTHOR]

Background and aims: Despite proven clinical efficacy of vedolizumab (VDZ) for inducing and maintaining remission in patients with Crohn’s disease (CD) and ulcerative colitis (UC), subgroups of patients have no therapeutic benefit from anti-α4β7 integrin therapy with VDZ. Within this study, we aimed to identify genetic, cellular, and immunological mechanisms that define response and failure to VDZ treatment. Methods: Intestinal RNA sequencing was performed in UC and CD patients before and at week 14 of VDZ therapy. α4β7 expression on peripheral and mucosal immune cells was assessed by flow cytometry and immunohistochemistry. Cellular modes of VDZ-mediated action were analyzed ex vivo and in VDZ-treated inflammatory bowel disease patients. Results: Transcriptome analysis showed an impairment of signaling cascades associated with adhesion, diapedesis, and migration of granulocytes and agranulocytes upon VDZ therapy. In non-remitters to VDZ therapy, a tissue destructive and leukocyte-mediated inflammatory activity with activation of TNF-dependent pathways was present, all of which were inhibited in remitters to VDZ. Clinical remission was associated with a significant reduction of α4β7 expression on Th2 and Th17 polarized mucosal CD4+ T cells at week 14 of VDZ therapy and with significantly higher numbers of α4β7-expressing mucosal cells prior to the initiation of VDZ therapy compared with non-remitters. Conclusion: Intestinal α4β7 expression prior to VDZ therapy might represent a biomarker that predicts therapeutic response to subsequent VDZ treatment. Due to high activation of TNF signaling in VDZ non-remitters, anti-TNF treatment might represent a promising therapeutic strategy in VDZ refractory patients. [ABSTRACT FROM AUTHOR]

Purpose: To identify prognostic factors, define evolving patterns of care, and the effect of targeted therapies in a larger contemporary cohort of renal cell carcinoma (RCC) patients with new brain metastases (BM).Methods and Materials: A multi-institutional retrospective institutional review board-approved database of 711 RCC patients with new BM diagnosed from January 1, 2006, to December 31, 2015, was created. Clinical parameters and treatment were correlated with median survival and time from primary diagnosis to BM. Multivariable analyses were performed.Results: The median survival for the prior/present cohorts was 9.6/12 months, respectively (P < .01). Four prognostic factors (Karnofsky performance status, extracranial metastases, number of BM, and hemoglobin b) were significant for survival after the diagnosis of BM. Of the 6 drug types studied, only cytokine use after BM was associated with improved survival. The use of whole-brain radiation therapy declined from 50% to 22%, and the use of stereotactic radiosurgery alone increased from 46% to 58%. Nonneurologic causes of death were twice as common as neurologic causes.Conclusions: Additional prognostic factors refine prognostication in this larger contemporary cohort. Patterns of care have changed, and survival of RCC patients with BM has improved over time. The reasons for this improvement in survival remain unknown but may relate to more aggressive use of local brain metastasis therapy and a wider array of systemic treatment options for those patients with progressive extracranial tumor. [ABSTRACT FROM AUTHOR]

Abstract: Some biologics can modulate cytokines that may lead to changes in expression of drug‐metabolizing enzymes and cause drug‐drug interactions (DDI). DDI potential of TV‐1106—an albumin‐fused growth hormone (GH)—was investigated. In this study, human blood was exposed to recombinant human growth hormone (rhGH) or TV‐1106, followed by isolation of the plasma and its application to human hepatocytes. While the treatment of blood with rhGH increased multiple cytokines, treatment of blood with TV‐1106 had no effect on any of the nine cytokines tested. The interleukin (IL)‐6 concentration was higher in the rhGH then in the TV‐1106‐treated plasma (P < .05). While rhGH had little or no effect on CYP1A2 or CYP2C19 mRNA but increased CYP3A4 mRNA twofold, TV‐1106 had little or no effect on cytochrome P450 (CYP) mRNAs in hepatocytes. Although the plasma from rhGH‐treated blood lowered CYP1A2 activity, the TV‐1106 plasma had no effect on CYP activities. The CYP1A2 activity was lower in the rhGH‐ then in the TV‐1106‐plasma treated hepatocytes (P < .05). The results indicated that fusing GH with albumin made TV‐1106 an unlikely participant of CYP1A2, CYP2C19 or CYP3A4‐facilitated, direct or cytokine‐driven DDI. [ABSTRACT FROM AUTHOR]

The present study aimed to review and discuss the recommended and recently suggested protocols by Iranian researchers for a long-term treatment of delayed complications of sulfur mustard (DCSM) in veterans. As indicated clinically, patients who suffer from delayed ocular complications of sulfur mustard (DOCS) benefit from treatments for dry eyes, therapeutic contact lenses, amniotic membrane transplantation; blepharorrhaphy, tarsorrhaphy, limbal stem cell transplantation; corneal transplantation, topical steroids, and immunosuppressive. In spite of penetrating keratoplasty, lamellar keratoplasty and keratolimbal allograft had a good long-term survival. Delayed respiratory complications (DRCS) are the most common effects and life-threatening in Iranian veterans. The recommended treatment protocols include regular clinical evaluations, respiratory physiotherapy and rehabilitation, N-acetyl cysteine; warm humidified air, long-acting β2-agonists, and inhaled corticosteroids. Azithromycin has also been effective in improving clinical conditions, pulmonary function tests, inflammatory indexes, and life quality of the veterans. Interferon gamma (IFN-γ) and helium: oxygen combination were also used in severe DRCS with good results. Some of the delayed cutaneous complications (DCCS) such as itching affects the quality of life of victims. Regular but not frequent showering and bathing, applying sunscreen compounds, topical corticosteroids, and systemic antihistamines reduce the problems of DCCS patients. Several compounds such as capsaicin cream, pimecrolimus, IFN-γ, phenol-menthol; Aloe vera/olive oil cream, cetirizine, doxepine, and hydroxyzine were evaluated in DCCS patients with some benefits. The physicians in charge of veterans emphasize the importance of a healthy lifestyle, appropriate financial/social/cultural supports, and a degree of reassurance and supportive care on the clinical improvement of patients. [ABSTRACT FROM AUTHOR]

Viral infections, including HIV, trigger the production of type I interferons (IFNs), which in turn, activate a signalling cascade that ultimately culminates with the expression of anti-viral proteins. Mounting evidence suggests that type I IFNs, in particular IFN-α, play a pivotal role in limiting acute HIV infection. Highly active anti-retroviral treatment reduces viral load and increases life expectancy in HIV positive patients; however, it fails to fully eliminate latent HIV reservoirs. To revisit HIV as a curable disease, this article reviews a body of literature that highlights type I IFNs as mediators in the control of HIV infection, with particular focus on the anti-HIV restriction factors induced and/or activated by IFN-α. In addition, we discuss the relevance of type I IFN treatment in the context of HIV latency reversal, novel therapeutic intervention strategies and the potential for full HIV clearance. [ABSTRACT FROM AUTHOR]

Background: Perioperative neurocognitive disorders (PND) result in long-term morbidity and mortality with no effective interventions available. Because interleukin-6 (IL-6), a pro-inflammatory cytokine, is consistently up-regulated by trauma, including after surgery, we determined whether IL-6 is a putative therapeutic target for PND in a mouse model.Methods: Following institutional approval, adult (12-14 weeks) male C57/Bl6 mice were pretreated with the IL-6 receptor (IL6R) blocking antibody tocilizumab prior to open tibia fracture with internal fixation under isoflurane anaesthesia. Inflammatory and behavioural responses in a trace fear conditioning (TFC) paradigm were assessed postoperatively. Separately, the effects of IL-6 administration or of depletion of bone marrow-derived monocytes (BM-DMs) with clodrolip on the inflammatory and behavioural responses were assessed. Blood brain barrier disruption, hippocampal microglial activation, and infiltration of BM-DMs were each assessed following IL-6 administration.Results: The surgery-induced decrement in freezing time in the TFC assay, indicative of cognitive decline, was attenuated by tocilizumab (P<0.01). The surgery-induced increase in pro-inflammatory mediators was significantly reduced by tocilizumab. Exogenously administered IL-6 significantly impaired freezing behaviour (P<0.05) and up-regulated pro-inflammatory cytokines; both responses were prevented by depletion of BM-DMs. IL-6 disrupted the blood brain barrier, and increased hippocampal activation of microglia and infiltration of BM-DMs.Conclusions: IL-6 is both necessary and sufficient to produce cognitive decline. Following further preclinical testing of its perioperative safety, the IL6R blocker tocilizumab is a candidate for prevention and/or treatment of PND. [ABSTRACT FROM AUTHOR]

Macrophage polarization is involved in the process of inflammation. Regulation of macrophage polarization is considered to be an effective method for the treatment of various inflammatory diseases. In our study, we investigated the potential molecular mechanism of the flavonoid compound LZ205, which exhibits anti-inflammatory property. Results showed that LZ205 significantly reduced M1 macrophage-associated proinflammatory cytokines secretion by regulating PI3K/AKT/mTOR signaling pathway without affecting M2 macrophage-associated cytokines mRNA levels. In vivo studies showed that LZ205 significantly inhibited M1 macrophages polarization in DSS-induced colitis and alum-induced murine peritonitis. Consistent with in vitro studies, LZ205 significantly blocked expression of PI3K, p-AKT and p-mTOR in colon tissues and peritoneal macrophages. Taken together, LZ205 exerts anti-inflammatory effect by inhibiting M1 macrophage polarization via regulating PI3K/AKT/mTOR signaling pathway. [ABSTRACT FROM AUTHOR]

Background: The aim was to establish expression profiles of microRNAs (miRNAs) in Peripheral Blood Mononuclear Cells (PBMC) and of plasma cytokines from the patients with hepatitis B virus related acute-on-chronic liver failure (HBV-ACLF) and high-risk of acute-on-chronic liver failure (ACLF) patients as well as healthy people and to examine the relationships between these profiles and clinical features. Methods: Herein, we collected PBMCs and plasma from peripheral blood of HBV-ACLF and ACLF patients as well as healthy people. Microarray, real-time qPCR, and ELISA assays were used. Results: In this study, we found 39 miRNAs including miR- 146a, miR-150, and miR-29 a downregulated and 5 miRNAs elevated in PBMCs from HBV-ACLF patients compared to healthy controls. However, elevated plasma levels of cytokines such as TNF-α, IFN-α, and TGF-β were found in PBMCs from HB V-ACLF patients compared with the controls, but no significant difference was found between the high-risk and control groups. MiR-146a, miR-150, miR-29a, PTA, and anti-HBc were positively correlated with the survival of ACLF patients, while TNF-α, IFN-α, INR, and TBiL were negatively correlated with the survival of these patients. Conclusions: Combined examination of miRNAs in PBMCs and cytokines in plasma together is a better method for monitoring and evaluating HBV-ACLF patients. [ABSTRACT FROM AUTHOR]

Background Atherosclerosis is characterized by chronic inflammation in vascular wall. Previous studies suggest that Kuwanon G (KWG) exerts anti-inflammatory activities. However, the effect of KWG on atherosclerosis remains unexplored. Aims To explore whether KWG affects macrophage foam cell formation in vitro and atherogenesis in vivo . Methods RAW 264.7 macrophages were stimulated with ox-LDL for 24 h to induce foam cell formation and treated with KWG. Foam cell formation was determined by ORO staining and enzymatic analysis. Pro-inflammatory cytokines mRNA levels were tested by Real-time PCR method. Further molecular mechanism was investigated using Western blot. In vivo , ApoE −/− mice were fed with high-fat diet and intraperitoneally injected with KWG. Atherosclerotic lesion was accessed by H&E and ORO staining. Plaque composition was evaluated by immunohistochemistry and Sirius Red staining. Serum lipid profile and inflammatory cytokines were evaluated by enzymatic method and ELISA. Results KWG significantly decreased intracellular lipid accumulation and inflammatory cytokines mRNA levels in macrophages through enhancing LXRα-ABCA1/ABCG1 pathway and inhibiting NFκB activation. Administrated with KWG remarkably reduced the atherosclerotic lesion areas and macrophage content in the plaque of high-fat diet fed ApoE −/− mice. KWG also reduced hyperlipidemia and serum inflammatory cytokines in vivo . Conclusion Taken together, these data highlight that KWG can attenuate atherosclerosis through inhibiting foam cell formation and inflammatory response. [ABSTRACT FROM AUTHOR]

GM-CSF has been portrayed as a critical cytokine in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) and, ostensibly, in multiple sclerosis. C57BL/6 mice deficient in GM-CSF are resistant to EAE induced by immunization with myelin oligodendrocyte glycoprotein (MOG)35-55. The mechanism of action of GM-CSF in EAE is poorly understood. In this study, we show that GM-CSF augments the accumulation of MOG35-55-specific T cells in the skin draining lymph nodes of primed mice, but it is not required for the development of encephalitogenic T cells. Abrogation of GM-CSF receptor signaling in adoptive transfer recipients of MOG35-55-specific T cells did not alter the incidence of EAE or the trajectory of its initial clinical course, but it limited the extent of chronic CNS tissue damage and neurologic disability. The attenuated clinical course was associated with a relative dearth of MOG35-55-specific T cells, myeloid dendritic cells, and neutrophils, as well as an abundance of B cells, within CNS infiltrates. Our data indicate that GM-CSF drives chronic tissue damage and disability in EAE via pleiotropic pathways, but it is dispensable during early lesion formation and the onset of neurologic deficits. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) modulates immune-related inflammatory responses to induce milder reactions leading to virus persistence. In this regard, the present study aimed to investigate the link between the HCV genotypes and the proinflammatory and regulatory cytokine levels. Ninety patients with hepatitis C infection (68 treatment-naive and 22 treated patients) and 76 healthy blood donors were studied. The serum levels of IFN-γ, IL-10, IL-17A, and IL-21 were measured by ELISA in the patients and healthy controls. IL-10, IL-17A, and IL-21 levels were significantly higher in HCV patients than in the healthy controls. The same cytokines were also higher in genotype 3a-infected patients compared with genotype 1a-infected patients. Interestingly, in treated patients, lower serum levels of IL-17A and IL-21 were detected in G3a-infected individuals, but not in those infected with G1a. G3a viral load displayed a significant correlation with IL-21 and IL-17A levels. In addition, G1a viral load correlated with IL-10 levels. In G3a-infected patients, a significant association was found between IL-17A serum levels and ALT. We found differences in IL-21 and IL-17A serum levels among HCV-infected patients which were genotype dependent. Since Th17-associated cytokines are associated with the progression of liver disease in HCV patients, IL-17A and IL-21 can be used as important biological markers for evaluating the immunopathogenesis of chronic hepatitis. Our results suggest that HCV G3a along with immune responses such as cytokines in HCV patients should be taken into account when interpreting clinical data and IFN-based therapeutic response. [ABSTRACT FROM AUTHOR]

Brain edema and the associated increase in intracranial pressure are major consequences of traumatic brain injury (TBI) that accounts for most early deaths after TBI. We recently showed that acute severe trauma to cultured astrocytes results in cell swelling. We further examined whether trauma induces cell swelling in neurons and microglia. We found that severe trauma also caused cell swelling in cultured neurons, whereas no swelling was observed in microglia. While severe trauma caused cell swelling in both astrocytes and neurons, mild trauma to astrocytes, neurons, and microglia failed to cell swelling. Since extracellular levels of glutamate are increased in brain post-TBI and microglia are known to release cytokine, and direct exposure of astrocytes to these molecules are known to stimulate cell swelling, we examined whether glutamate or cytokines have any additive effect on trauma-induced cell swelling. Exposure of cultured astrocytes to trauma caused cell swelling, and such swelling was potentiated by the exposure of traumatized astrocytes to glutamate and cytokines. Conditioned medium (CM) from traumatized astrocytes had no effect on neuronal swelling post-trauma, while CM from traumatized neurons and microglia potentiated the effect of trauma on astrocyte swelling. Further, trauma significantly increased the Na–K–Cl co-transporter (NKCC) activity in neurons, and that inhibition of NKCC activity diminished the trauma-induced neuronal swelling. Our results indicate that a differential sensitivity to trauma-induced cell swelling exists in neural cells and that neurons and microglia are likely to be involved in the potentiation of the astrocyte swelling post-trauma. [ABSTRACT FROM AUTHOR]

Type 2 immune responses have evolved to sense and respond to large, non-replicating infections or non-microbial noxious compounds in tissues. The development of these responses therefore depends upon highly coordinated and tightly regulated tissue-residing cellular sensors and responders. Multiple exposure to type 2 helper T cell (Th2)-inducing stimuli further enhances both the diversity and potency of the response. This review discusses advances in our understanding of the interacting cellular subsets that comprise both primary and secondary type 2 responses. Current knowledge regarding type 2 immune responses in the lung are initially presented and are then contrasted with what is known about the small intestine. The studies described portray an immune response that depends upon well-organized tissue structures, and suggest their modulation as a therapeutic strategy. [ABSTRACT FROM AUTHOR]

Polybrominated diphenyl ethers (PBDEs) are pollutants that may increase the risk of preterm birth. In previous studies, we found that a mixture of PBDEs altered the expression of biomarkers for preterm birth by the placenta. However, there are 209 different PBDE congeners with different tissue distributions. How these different congeners may alter the production of immunomodulators by the placenta that help to maintain the survival of the fetal allograft is unclear. Therefore, we compared the effects 5 common congeners on basal and bacteria-stimulated cytokine production by the placenta. Placental explant cultures were incubated with 20 μM of PBDE congeners 47, 99, 100, 153, 209 or vehicle in the presence and absence of Escherichia coli for 20 h. Conditioned medium was harvested and concentrations of IL-1β, TNF-α, IL-6, sgp130, HO-1, IL-10, BDNF, and 8-IsoP quantified. For unstimulated cultures, all congeners, except for PBDE-47, reduced the production of IL-1β and IL-6 production was enhanced by PBDE-153. BDNF concentrations tended to be reduced by most PBDE congeners and IL-10 production was enhanced by PBDE-99, −153, and −209. 8-IsoP production was enhanced by PBDE-153, but not the other congeners. For bacteria-stimulated cultures, PBDE-47 increased IL-1β production and PBDE-47, −153, and −209 tended to reduce TNF-α production. IL-6 production was enhanced by all PBDEs except 153. IL-10 production was enhanced by all congeners except for PBDE-47. All congeners significantly enhanced BDNF and 8-IsoP. These results suggest that PBDEs can alter the expression of placental biomarkers in a congener and infection-dependent manner. [ABSTRACT FROM AUTHOR]

We performed a prospective cohort study in 197 pregnant women. Peripheral blood was collected between 5 and 16 weeks of gestation. Intracellular cytokine analysis and immunophenotype were performed by flow-cytometry. Serum levels of cytokines and chemokines were analyzed by multiplex assay. 86 patients were eligible for the analysis and 10.5% (n = 9) developed preeclampsia. Patients with preeclampsia had significantly higher percentage of CD3 + CD4 + TNFα + T helper (Th) 1 cells (45.4 ± 10.3 vs 37.1 ± 8.5, P = 0.032) and CD3 + CD4 + IL17 + Th 17 cells (2.4 ± 1.3 vs 1.6 ± 1.1, P = 0.029) when compared to those of patients without preeclampsia. CD3 + CD4 + CD25 + CD127 dim/− T regulatory cells (Treg) cells (5.7 ± 1.2% vs 7.0 ± 1.6%, P = 0.015) were significantly lower in patients with preeclampsia when compared to those without preeclampsia. Patients with preeclampsia had significantly higher TNFα/IL-10 cell ratio (43.8 ± 10.3 vs 34.3 ± 7.9, P = 0.005) and Th17/Treg cell ratio (0.5 ± 0.3 vs 0.2 ± 0.2, P = 0.011) when compared to those of patients without preeclampsia. IL-8 and Macrophage inflammatory protein (MIP)-1α serum levels were significantly higher in patients with preeclampsia when compared with patients without preeclampsia (Median = 341.0 vs 87.6, U = 152, P = 0.020 and Median = 35.7 vs 17.7, U = 120, P = 0.029 respectively). Serum MCP-1 levels were significantly lower in patients with preeclampsia when compared with patients without preeclampsia (Median = 233.8 vs 390.9, U = 183, P = 0.021). The logistic regression predictive model combining TNFα/IL-10 ratios, IL-8 and MCP-1 serum levels had the best performance (AUC = 0.886, 95%CI 0.8–0.9). We concluded that elevated Th1 and Th17 cell percentages, elevated TNFα/IL-10 and Th17/Treg cell ratios and decreased Treg cell percentages in early pregnancy are associated with preeclampsia. [ABSTRACT FROM AUTHOR]

Abstract: Background: The role of immune activation in Functional Dyspepsia (FD) patients without previous infection is unclear. We compare the gastric and circulating brain‐derived neurotropic factor (BDNF), receptor potential vanilloid type (TRPV) families and various cytokines in FD patients. Methods: Consecutive adult FD patients (Rome III) with no recent history of gastroenteritis and asymptomatic healthy controls were recruited for upper endoscopy. Subjects with GERD and IBS as predominant symptoms, diabetes mellitus, current or previous Helicobacter pylori infection, psychiatric illness and recent use of NSAID or PPI were excluded. Corpus biopsies and serum samples were collected. Key Results: Forty three [M:F=8:35, mean age: 35.0 (9.3)] FD patients were compared with 23 healthy controls [M:F=8:15, mean age: 36.6 (10.2)]. FD patients had postprandial distress syndrome (PDS) as predominant sub‐type (PDS: 36, EPS: 2). There was no significant difference in the median inflammation score (FD:0 (0‐1) vs Control:0 (0‐1), P=.79). However, FD patients had significantly higher mRNA expression of TRPV1 (FD:0.014±0.007, Control:0.003±0.001, 4.6 fold, P=.02) and TRPV2 (FD:0.012±0.006, Control:0.003±0.001, 4 fold, P=.02) compared to controls. The serum (FD:258.0±12.3 ng ml−1, Control:319.7±18.1 ng ml−1, P<.01) and gastric BDNF mRNA (FD:0.06±0.008, Control:0.092±0.01, 0.65 fold, P=.02)levels significantly lower in FD patients. Secretion of cytokines (IL‐4, IL‐5, IL‐6, IL‐8, IL‐10, G‐CSF, TGF‐β2, MCP‐1)was also highly correlated with dyspeptic symptoms in patients with FD. Conclusions & Inferences: Despite lacking gastric mucosal inflammation, up‐regulation of TRPV1 and TRPV2, down‐regulation of BDNF were observed in FD patients. These suggest that immune alteration may contribute to the pathogenesis of FD without any previous infection. [ABSTRACT FROM AUTHOR]

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatological disease of childhood. Despite the current availability of potent disease-modifying anti-rheumatic medications, most children still experience a chronic course with prolonged periods of active disease. Goals for treatment should include disease remission with optimal physical functioning allowing children to lead normal lives without structural joint damage. However, recent studies demonstrate only moderate rates of remission, indicating that JIA is not as benign as previously thought. The probability of attaining remission within 5 years is approximately 50% across all JIA categories except for polyarthritis when the outlook is significantly worse. Longer term, about 50% of adults with JIA suffer from persistent inflammation and disability. There is a shift towards early aggressive treatment with the intention to switch off inflammation since there may be a ‘window of opportunity’ before the disease becomes chronic. There is clear evidence for improved outcome in adult patients treated with this approach (‘treat to target’) but limited paediatric evidence to date. The explosion in anticytokine agents for treatment of disease resistant to conventional therapy has expanded our armamentarium, improving short term clinical outcomes, but it is still unclear whether we have achieved significant improvements in outcome longer term. This review describes the disease and current and longer-term data on outcomes for this common chronic childhood condition. [ABSTRACT FROM AUTHOR]

Recurrent miscarriage is defined as the loss of 3 or more consecutive pregnancies; however, the underlying immunologic mechanisms that trigger pregnancy loss remain largely unelucidated. Galectin-9 (Gal-9) may modulate a variety of biologic functions and play an important role in Th1/Th2 immune deviation. To analyze the mechanism of Gal-9 in abortion, we used the classical abortion-prone mouse model (DBA/2-mated CBA/J mice) to detect the expression of Gal-9 at the maternal-fetal interface. We also mimicked the immune environment of pregnancy by culturing trophoblast cells with peripheral blood mononuclear cells (PBMCs) to explore how Gal-9 might be involved in the pathogenesis of abortion. We found that the expression levels of Gal-9 in abortion-prone matings were lower than that for controls. Using a coculture system, we detected a Th1 preponderance in the coculture from abortion-prone matings. Furthermore, Gal-9 blockade augmented the imbalance of Th1/Th2 immunity in abortion-prone matings by promoting the secretion of Th1-derived cytokines in coculture, while there was a Th2 preponderance when we administered recombinant Gal-9. In conclusion, our results suggest that the Gal-9 signal is important for the regulation of PBMC function toward a Th2 bias at the maternal-fetal interface, which is beneficial for the maintenance of a normal pregnancy. [ABSTRACT FROM AUTHOR]

Adiponectin, a metabolically-active cytokine secreted from adipose tissue, is reported to have anti-apoptotic effects on β-cells as well as anti-hyperglycemic effects through adiponectin receptor signaling. However, the anti-apoptotic effects of adiponectin on β-cells have not been confirmed in established diabetic models, and the anti-hyperglycemic effects and their associated signal cascades remain controversial. To investigate the effects of adiponectin on β-cell protection and its down-stream signaling events, we have generated β-cell-specific rat insulin promoter (RIP)-AdipoR1 transgenic mice (AdipoR1 mice), in which the adiponectin receptor, AdipoR1, is overexpressed in β-cells in a manner synchronous with insulin demand. AdipoR1 mice were then mated with Akita mice, a diabetes model in which β-cell apoptosis results from endoplasmic reticulum (ER) stress. AdipoR1 protein expression and localization in islets from AdipoR1 mice as well as in an AdipoR1-transfected mouse insulinoma cell line were confirmed, as was the activation of both AMPK and Akt in AdipoR1 mice by adiponectin. Nevertheless, there were no significant differences in Ad lib feed and fasting blood glucose levels, or in glucose tolerance tests, between Akita mice [Ins2Akita (C96Y) +/- mouse model] and AdipoR1/Akita and from 4 weeks to 10 weeks of age. Similarly, pancreatic insulin contents of AdipoR1/Akita mice were not significantly different from those in Akita mice from 15 to 20 weeks of age, but they were significantly lower than in wild-type mice. Immunostaining for insulin and subsequent electron microscopy showed that β-cell destruction in AdipoR1/Akita mice was not markedly improved in comparison with that in Akita mice. Serum adiponectin concentrations were confirmed to be extremely high (> 30 μg / ml) compared with the Kd value (0.06 μg / ml) in all mouse groups at 15 to 20 weeks of age. Therefore, although the physiological levels of adiponectin are sufficient to activate AMPK and Akt when AdipoR1 is overexpressed in β-cells, yet adiponectin cannot protect β-cells in Akita mice from ER stress-induced destruction. [ABSTRACT FROM AUTHOR]

The most important morphological characteristic of infections caused by M. avium subsp. hominissuis (MAH) is granuloma formation. The growth of mycobacteria is in accordance with anti-bacterial effector mechanisms of the host within granuloma. The most important cytokines for „orchestrating"the host defense are interferon γ (INF-γ), tumor necrosis factor α (TNF-α) and transforming growth factor β1 (TGF-β1). Myofibroblasts that make up a peripheral layer of granuloma largely express receptors for TGF-β1. This cytokine is believed to affect the induction of myofibroblast proliferation. The aim of this paper is to point out the importance of myofibroblasts in the formation and sustainability of granuloma during natural infection of pigs with M. avium subsp. hominissuis. Examinations have been performed on the samples of Lnn. jejunales, Lnn. ileocolici and Lnn. colici of 100 pigs with a positive tuberculin skin test. The molecular method confirmed the presence of a genome M. avium subsp. hominissuis. The microscopic examination of lymph node samples stained by the routine hematoxyilin-eosin (HE) method, showed the presence of granulomatous lymphadenitis. The method of double immunohistochemical staining revealed that myofibroblasts which express TGF-β1 receptor type I (TGF-β1RI) and α smooth muscle actin (α SMA) have an important role in the morphogenesis of granulomatous lymphadenitis in pigs infected with MAH. [ABSTRACT FROM AUTHOR]

Aim There are no beneficial therapies except for emergency liver transplantation for acute liver failure (ALF). However, in Japan, which has a serious problem in the shortage of donor livers, therapies other than transplantation must be further investigated for patients with ALF. Pro-inflammatory cytokines promoting tissue destruction are predominant at an early phase of ALF. Corticosteroid (CS) influences monocyte/macrophage differentiation, by suppressing pro-inflammatory genes, indicating CS treatment might be beneficial during the early phase of ALF. Our aim was to elucidate the efficacy of CS pulse therapy in decreasing pro-inflammatory cytokine levels in the early stage of ALF. Methods Ten consecutive adult Japanese patients with fulminant hepatitis in the early stage, three treated with artificial liver support (ALS) and CS pulse therapy (ALS + CS group) and seven treated with ALS (ALS group), were enrolled. Clinical and biochemical data on admission were matched between the groups and retrospectively analyzed for serum concentrations of interleukin-6, tumor necrosis factor-α, and interleukin-1β over a 2-week period. Results Mean cytokine levels on admission were not different between the two groups. Tumor necrosis factor-α was significantly reduced on day 7 in patients with CS. Serum levels of pro-inflammatory cytokines tended to be reduced in patients with CS compared to those without during the observation period, although the differences were not significant. Conclusions It might be possible that introduction of CS pulse therapy in the early stage of ALF could reduce levels of pro-inflammatory cytokines, which might inhibit the cascade of progression of ALF. [ABSTRACT FROM AUTHOR]

Cytokine-induced killer (CIK) cells are in vitro-expanded cells harboring potent toxicity against tumor cells. Recently, it was identified that the cytotoxicity and proliferation of CIK cells are restricted by a prolonged CIK cell culture period. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) serves a negative role in T cell activation and proliferation. This study aims to determine whether CTLA-4 expression is associated with the inhibition of CIK cells. CIK cells were generated from peripheral blood mononuclear cells (PBMCs), and CTLA-4 shRNA (shCTLA-4) lentivirus was applied to knockdown CTLA-4 expression in CIK cells. The proliferation of CIK cells was evaluated following shCTLA-4 lentiviral transduction, and the cytotoxicity of CIK cells was investigated using the CytoTox 96 Non-Radioactive Cytotoxicity assay. The expression of CTLA-4 in CIK cells was significantly increased, compared with that in PBMCs. The shCTLA-4 lentivirus efficiently knocked down the expression of CTLA-4 in CIK cells. The shCTLA-4 lentivirus transduction of CIK cells promoted the proliferation of CIK cells in vitro (3.18±0.19-fold vs. 2.42±0.29-fold). Furthermore, the cytotoxicity of shCTLA-4 lentivirus-transduced CIK cells was significantly improved when compared with that of control shRNA lentivirus-transduced CIK cells (54.5±2.13% vs. 30.5±1.67%). Thus, the suppression of CTLA-4 expression increases cytotoxicity and ex vivo expansion of CIK cells, which indicates a clinical significance for CTLA-4 blockade in CIK cell therapy. [ABSTRACT FROM AUTHOR]

Mitochondrial factor and cell cytokines play important roles in the incidence of vascular dementia (VD), but their correlations with inflammatory and mitochondrial factors and the role of both in the kidney essence deficiency pattern and phlegm turbidity blocking orifice pattern are not clear. This study was aimed at studying the correlations between the serum mitochondrial factor and cell cytokines with TCM Syndrome Scale in vascular dementia. According to the inclusion criteria we collected 108 vascular dementia patients which were divided into the kidney essence deficiency pattern and phlegm turbidity blocking orifice pattern based on the TCM Syndrome Scale. We measured serum tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-18 (IL-18) concentration using an enzyme-linked immunosorbent assay (ELISA) and serum malondialdelyde (MDA) and superoxide dismutase (SOD) was quantified according to instructions of kits from the 108 patients (45 in kidney essence deficiency pattern, 63 in phlegm turbidity blocking orifice pattern). The scale scores were assessed using TCM Syndrome Scale, MMSE, Hachinski, Barthel, BBS, CDR. There was a signifi- cant difference on the scores of CDR and the factors of the memory, judgment, social affairs, personal care, family and hobbies among the two groups, The means of kidney essence deficiency group was higher than that of phlegm turbidity blocking orifice pattern group. IL-18 and SOD in the phlegm turbidity blocking orifice group was higher than those in the kidney essence deficiency pattern; IL-6 in phlegm turbidity blocking orifice pattern group was lower than that in the kidney essence deficiency pattern. By logistic regression analysis, we demonstrated that high concentration of IL-6, TNF-α, and MDA were associated with increased TCM syndrome scores in two groups, while IL-6, IL-18, TNF-α, SOD were associated with decreased MMSE, Barthel. Our study support the notion that IL-6 plays a more important role in the integral of kidney essence deficiency pattern, IL-18 is a more important factor in phlegm turbidity blocking orifice pattern. The results can be used as the theoretical basis of traditional Chinese Medicine prescription and pharmacological research in future, through decrease in IL-6 lever and increase in SOD in integral kidney essence deficiency pattern, and IL-18 as the main anti inflammation index in phlegm turbidity blocking orifice pattern. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a serious threat for the aging society. In this study, we examined the preventive effect of the total prenylflavonoids (TPFB) prepared from the dried fruits of Psoralea corylifolia L., using an age-related AD mouse model SAMP8. We found that long-term dietary TPFB at 50 mg/kg·day significantly improved cognitive performance of the SAMP8 mice in Morris water maze tests, similar to 150 mg/kg·day of resveratrol, a popular neuro-protective compound. Furthermore, TPFB treatment showed significant improvements in various AD markers in SAMP8 brains, which were restored to near control levels of the normal mice, SAMR1. TPFB significantly reduced the level of amyloid β-peptide 42 (Aβ42), inhibited hyperphosphorylation of the microtubule-associated protein Tau, induced phosphorylation of Ser9 of the glycogen synthase kinase 3β (GSK-3β), and decreased the expression of the proinflammatory cytokines TNFα, IL-6, and IL-1β. Finally, TPFB also markedly reduced the level of serum derivatives of reactive oxygen metabolites (d-ROMs), a biomarker of oxidative stress in vivo. These results showed that dietary TPFB could effectively prevent age-related cognitive deficits and AD-like neurobiochemical changes, and may have a potential role in the prevention of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor-α ( TNF-α) is a pleiotropic inflammatory cytokine that exerts potent cytotoxic effects on solid tumor cells, while not affecting their normal counterparts. It is also known that TNF-α exerts many of its biological functions via interaction with specific receptors. To understand the potential roles of intrinsic disorder in the functioning of this important cytokine, we explored the peculiarities of intrinsic disorder distribution in human TNF-α and its homologs from various species, ranging from zebrafish to chimpanzee. We also studied the peculiarities of intrinsic disorder distribution in human TNF-α receptors, TNFR1 and TNFR2. Analysis revealed that cytoplasmic domains of TNF-α and its receptors are expected to be highly disordered. Furthermore, although the sequence identities of analyzed TNF-α homologs range from 99.57% (between human and chimpanzee proteins) to 22.33% (between frog and fish proteins), their intrinsic disorder profiles are characterized by a remarkable similarity. These observations indicate that the peculiarities of distribution of the intrinsic disorder propensity within the amino acid sequences are evolutionary conserved, and therefore could be of functional importance for this family of proteins. We also show that disordered and flexible regions of human TNF-α and its TNFR1 and TNFR2 receptors are crucial for some of their biological activities. [ABSTRACT FROM AUTHOR]

The probiotic strains of Lactobacillus casei IMV B-7280, Bifidobacterium animalis VKL, B. animalis VKB (individually) or L. casei IMV B-7280 - B. animalis VKB - B. animalis VKL composition balanced the Th1/Th2 cytokines production at normal condition and in the cases of experimental intravaginal staphylococcosis in BALB/c mice in different periods of observation. L. casei IMV B-7280 and B. animalis VKB (individually) at normal condition increased the Th1 type cytokines interleukin (IL)-12 and interferon (IFN)-γ production. Instead, B. animalis VKL after injection into intact mice did not affect the IL-12 production but slightly increased the IFN-γ production. In the cases of experimental intravaginal staphylococcosis in mice the balancing of Th1/Th2 immune response under the influence of L. casei IMV B-7280 is due to increased production of IL-12 and IFN-γ, as well as decreased Th2 type cytokine IL-4 production. The IL-12 and IFN-γ production in staphylococcus-infected mice that received B. animalis VKL or B. animalis VKB (individually) was increased, but these probiotic bacteria had no significant effect on IL-4 production. Under the influence of L. casei IMV B-7280, B. animalis VKB, B. animalis VKL (individually) in the cases of experimental intravaginal staphylococcosis in mice the IL-4/IFN-γ ratio was significantly decreased. The shift from Th2 to Th1 type cytokines production was also observed in staphylococcus-infected mice that received L. casei IMV B-7280 - B. animalis VKB - B. animalis VKL composition. The IL-12 and IFN-γ production was increased, instead, IL-4 production as well as IL-4/IFN-γ ratio were decreased in mice that received this probiotic composition in different periods of observation. So, L. casei IMV B-7280, B. animalis VKB and B. animalis VKL (individually) and L. casei IMV B-7280 - B. animalis VKB - B. animalis VKL composition are promising to create highly effective immunobiotics with immunomodulatory effect that are able to balance Th1/Th2 type of immunity by shifting the cytokine profile with decreased the IL-4/IFN-γ ratio. [ABSTRACT FROM AUTHOR]

Regulatory FOXP3+ T cells (Tregs) constitute 5% to 10% of T cells in the normal human skin. They play an important role in the induction and maintenance of immunological tolerance. The suppressive effects of these cells are exerted by various mechanisms including the direct cytotoxic effect, anti-inflammatory cytokines, metabolic disruption, and modulation of the dendritic cells function. The deficiency of Treg cells number or function are one of the basic elements of the pathogenesis of many skin diseases, such as psoriasis, atopic dermatitis, bacterial and viral infections. They also play a role in the pathogenesis of T cell lymphomas of the skin (cutaneous T cell lymphomas - CTCL), skin tumors and mastocytosis. Here, in the second part of the cycle, we describe dysfunctions of Tregs in selected skin diseases. [ABSTRACT FROM AUTHOR]

Abstract. Lysozyme is commonly found in spots where bacterial infections are most likely to enter the body. Earlier we found that lysozyme possesses five antimicrobial peptide motifs in its N-terminal region which can be generated by newborn pepsin. In this study, we explore the role of these peptides in the anti-inflammatory activity of lysozyme. The five peptides, helix1 (H1), helix2 (H2), H1 and H2 connected with a loop (HLH), H2 extended with either 2 β-strands (H2–S12) or 3 β-strands (H2–S13), were synthesized and examined for anti-inflammatory action. The five peptides dose-dependently decreased, to different degrees, expression of pro-inflammatory cytokines, TNF-α, IL-6 and IL-1β, in lipopolysaccharide (LPS)- or interferon-gamma (INF-γ)-stimulated mouse macrophage cells (RAW264.7). The HLH peptide and its individual helices (H1 and H2) were markedly the most potent anti-inflammatory. When macrophage cells were stimulated with live bacteria ( E . coli ), H1 peptide was the most powerful suppressor of TNF-α and IL-6 expression, providing evidence that the peptide is able to antagonize the pathogen-induced inflammatory response. Receptor binding assay and docking simulation provided evidence that H1 peptide bind specifically to the pocket for endotoxin binding of the toll-like receptor 4 (TLR-4) of macrophage. The results demonstrate, for the first time, the molecular basis of anti-inflammatory action of lysozyme that N-terminal helical peptides are the main contributors. This exciting finding offers new classes of therapeutic peptides with potential in the treatment of infection-induced inflammatory diseases. [ABSTRACT FROM AUTHOR]

Chronic pain is the most prominent and disabling symptom in the patients with osteoarthritis (OA), and the underlying mechanism largely remains unclear. Interleukin-6 (IL-6), a proinflammatory cytokine, is critically involved in the development and maintenance of central sensitization in several rodent models of chronic pain. The present study aims to elucidate the IL-6 mediated neurological adaptation in dorsal horn in the rat with monosodium iodoacetate (MIA) – induced OA. Significant upregulation of IL-6 expression was detected in the dorsal horn in the modeled rats. Blockade of IL-6 function by tocilizumab markedly suppressed the activation of astrocytes and microglia in the ipsilateral dorsal horn, reduced c-Fos immunoreactivity in dorsal horn neurons, and attenuated the upregulation of glutamate receptor subunits GluR1 and NR2B in dorsal horn in the rats with MIA-induced OA. It was further reported that administration of tocilizumab significantly improved the performance in weight-bearing test and mitigated the mechanical allodynia in the modeled rats. These data illustrated spinal IL-6 mediated mechanism underlying the chronic pain, and proposed the potential therapeutic effect of tocilizumab on the chronic pain in the setting of OA. [ABSTRACT FROM AUTHOR]

Among clinical studies, randomized studies as well as well-designed observational studies are providing the highest quality data. In addition, these studies represent a good opportunity to examine biomarkers of ictogenesis and epileptogenesis. To date, no validated molecular or cellular biomarker exists for any aspect of epilepsy. We provide an overview of the inflammatory biomarkers under investigation in prospective clinical studies in epilepsy: proinflammatory cytokines in prolonged febrile seizure; High Mobility Group Box 1 ( HMGB1) as a prognosis biomarker in epilepsy and the interaction between inflammation and metabolism, in particular, iron metabolism, in epilepsy. The designs of the European Union EPISTOP project following prospectively patients with tuberous sclerosis from birth to the start of the epilepsy and of the Standard and New Antiepileptic Drugs- II study illustrate how such studies can be used to find new inflammatory biomarkers of ictogenesis and epileptogenesis. If we want to bridge the current gap between having numerous biomarker candidates from preclinical studies and their selective use in clinical practice, we need to explore multiple biologic systems, not just including inflammation. In addition, it is crucial that those involved in the design and support of relevant clinical studies recognize this gap and act accordingly, and in the interests of improving the diagnosis and prognosis for epilepsy. [ABSTRACT FROM AUTHOR]

ABSTRACT Background and objective Acute eosinophilic pneumonia ( AEP) is characterized by a massive pulmonary infiltration of eosinophils. Mechanisms regulating the selective accumulation of eosinophils in AEP have not been fully established. The objective of this study was to evaluate the mechanisms of eosinophil accumulation in alveolar spaces through examination of bronchoalveolar lavage fluid ( BALF) from AEP patients ( AEP-BALF). Methods Eosinophils were isolated from the blood of healthy subjects and were placed on a human pulmonary microvascular endothelial cell monolayer cultured on Transwell filters (Coster, Cambridge, MA, USA). A saline control solution or BALF from patients with AEP, sarcoidosis or hypersensitivity pneumonitis was applied to the lower compartment, and the transendothelial migration of the eosinophils was evaluated. The concentrations of cytokines and chemokines in BALF were also measured. Results Transmigration of eosinophils across endothelial cells was only induced by the AEP-BALF. This transmigration was blocked by anti-β2 integrin mAb. The concentrations of eotaxin-2 and monocyte chemotactic protein ( MCP)-4, which are CC chemokine receptor ( CCR) 3 ligands, were elevated in the AEP-BALF, and anti- CCR3 mAb or anti- MCP-4 mAb inhibited the AEP-BALF-induced transmigration of eosinophils. Furthermore, the concentration of leukotriene ( LT) B4 was increased in the AEP-BALF, and an LTB4 receptor antagonist partially suppressed the AEP-BALF-induced transmigration of eosinophils. Conclusion These findings suggest that CCR3 ligands including eotaxin-2 and MCP-4, and LTB4 play a role in the accumulation of eosinophils in AEP. [ABSTRACT FROM AUTHOR]

Natural cytokine-specific autoantibodies (c-aAb) have been measured in healthy and diseased individuals, and have been considered as both endogenous immune-regulators and pathogenic factors. Overall, the etiology and potential pathology of c-aAb are still undefined. To further characterize the sero-prevalence, predictors and consequences of high c-aAb levels, we performed the largest population-based study of c-aAb to date, using participants and epidemiological data from the Danish Blood Donor Study. Using a validated bead-based multiplex assay we assessed plasma levels of IL-1α, IL-6, IL-10, IFNα and GM-CSF-specific c-aAb in 8,972 healthy blood donors. Trace levels of at least one of the investigated c-aAb could be measured in 86% of the participants. The presence of high levels of potentially inhibitory c-aAb was generally associated with increasing age and male or female sex, depending on the c-aAb in question. A negative correlation between high levels of IL-6-specific c-aAb and plasma levels of C-reactive protein was observed, indicating cytokine-neutralizing levels of c-aAb in healthy blood donors. There was no substantial correlation between high levels of the five individual c-aAb investigated in this study. These data suggest that autoimmunity against endogenous cytokines is a relatively common phenomenon in healthy individuals, and that predictive factors for high, potentially neutralizing c-aAb levels vary depending on the cytokine in question, and may differ from predictors of general c-aAb presence. [ABSTRACT FROM AUTHOR]

The characteristic hemorrhages of acute promyelocytic leukemia (APL) are caused in part by the high expression of tissue factor (TF) on leukemic cells, which also produce TNF and IL-1β, proinflammatory cytokines known to increase TF in various cell types. Exposure of NB4 cells, an APL cell line, to all-trans retinoic acid (ATRA) or arsenic trioxide (ATO) rapidly and strongly reduced TF mRNA. Both drugs also reduced TNF mRNA, but later, and moreover increased IL-1β mRNA. The effect on procoagulant activity of cells and microparticles, as measured with calibrated automated thrombography, was delayed and only partial at 24 h. TNF and IL-1β inhibition reduced TF mRNA and activity only partially. Inhibition of the inflammatory signaling intermediate p38 reduced TF mRNA by one third but increased TNF and IL-1β mRNA. NF-κB inhibition reduced, within 1 h, TF and TNF mRNA but did not change IL-1β mRNA, and rapidly and markedly reduced cell survival, with procoagulant properties still being present. In conclusion, although we provide evidence that TNF, IL-1β, and their signaling intermediates have a regulatory function on TF expression by NB4 APL cells, the effect of ATRA and ATO on TF can only partially be accounted for by their impact on these cytokines. [ABSTRACT FROM AUTHOR]

The serum levels of sixteen cytokines related to innate immunity, Th1, Th2 and Th17 cells in the sera of 44 patients with Behcet’s Disease (BD) and 44 healthy controls have been investigated using the cytokine array technique. Among the cytokines related to innate immunity, the levels of IL-1α, IL-1 β, IL-6, IL-12, IL-15 and TNF-α were statistically higher in BD patients than healthy controls. In the case of Th1- and Th17-related cytokines, IL-2, IFN-γ, IL-17 and IL-23 were significantly higher in patients. From Th2-related cytokines, only IL-13 showed statistically higher levels in patients than controls. Among different evaluated cytokines, the differences in IL-1 α, IL-1 β, IL-6 and Ʃinnate-related cytokines were more prominent between cases and controls. In addition, the results showed that Ʃinnate- and ƩTh17-related cytokines are better indicators of cytokines imbalances in BD than each one of the innate- and Th17-related cytokines. Moreover, disease activity score and clinical activity index can also be affected by the levels of pro-inflammatory (IL-6) and anti-inflammatory (IL-4) cytokines. In conclusion, the results revealed that imbalances in the expression of innate immunity- as well as Th1- and Th17-related cytokines may play not only a pivotal role in BD pathogenesis but also can be important in disease severity. [ABSTRACT FROM AUTHOR]

Immunological tolerance between fetal allograft and mother is crucial for pregnancy establishment and maintenance; however, these mechanisms particularly those during the latter part of pregnancy have not been definitively elucidated. The aim of this study was to examine the presence and potential function of innate immunity characteristic to the middle to late pregnancy. We first characterized up-regulated proteins in decidua from day 11 pregnant (P11) mice using 2D-PAGE, followed by MALDI-TOF/MS analysis. These analyses identified increased complement component 3 (C3) and its derivatives in P11 decidua. We then found that in the decidual tissues, C3 mRNA increased on P15 and remained high on P19. C3 is converted to C3b and then iC3b by complement component factor I (Cfi) and complement receptor 1-like protein (Crry), both of which were present in P19 placentas. In addition, iC3b proteins and its receptor CR3 (Cd11b/Cd18) in decidual and placental tissues increased toward the latter phase of pregnancy. Moreover, CR3 subunit CD11b protein was predominantly localized to spongiotrophoblast layer in the P19 placenta. Because iC3b is known to induce anti-inflammatory cytokine production, the analysis was extended to examine changes in pro- and anti-inflammatory cytokines, Il12, Il10, and Tgfb1. Il12 expression decreased in P15 and P19 placenta, while high mRNA expression of Il10 and Tgfb1 was found in P19 placental tissues. Furthermore, placental Il10 and Tgfb1 mRNAs were down-regulated when pregnant mice were treated with an anti-C3 antibody, detecting C3, C3b and iC3b. These results indicated that C3 derivatives, in particular, iC3b and its receptor CR3 were up-regulated at the fetal-maternal interface, and suggest that iC3b may regulate the placental expression of anti-inflammatory cytokines, IL10 and TGFB1, during the latter phase of pregnancy. [ABSTRACT FROM AUTHOR]

Multiple myeloma is the second most common hematological malignancy. Despite all the progress made in treating multiple myeloma, it still remains an incurable disease. Patients are left with a median survival of 4–5 years. The combined treatment of multiple myeloma with histone deacetylase inhibitors and cytokine-induced killer cells provides a promising targeted treatment option for patients. This study investigated the impact of a combined treatment compared to treatment with histone deacetylase inhibitors. The experiments revealed that a treatment with histone deacetylase (HDAC) inhibitors could reduce cell viability to 59% for KMS 18 cell line and 46% for the U-266 cell line. The combined treatment led to a decrease of cell viability to 33% for KMS 18 and 27% for the U-266 cell line, thus showing a significantly better efficacy than the single treatment. [ABSTRACT FROM AUTHOR]

TNF blockers are highly efficacious at dampening inflammation and reducing symptoms in rheumatic diseases such as rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis, and also in nonrheumatic syndromes such as inflammatory bowel disease. As TNF belongs to a superfamily of 19 structurally related proteins that have both proinflammatory and anti-inflammatory activity, reagents that disrupt the interaction between proinflammatory TNF family cytokines and their receptors, or agonize the anti-inflammatory receptors, are being considered for the treatment of rheumatic diseases. Biologic agents that block B cell activating factor (BAFF) and receptor activator of nuclear factor-κB ligand (RANKL) have been approved for the treatment of systemic lupus erythematosus and osteoporosis, respectively. In this Review, we focus on additional members of the TNF superfamily that could be relevant for the pathogenesis of rheumatic disease, including those that can strongly promote activity of immune cells or increase activity of tissue cells, as well as those that promote death pathways and might limit inflammation. We examine preclinical mouse and human data linking these molecules to the control of damage in the joints, muscle, bone or other tissues, and discuss their potential as targets for future therapy of rheumatic diseases. [ABSTRACT FROM AUTHOR]

Combination therapies involving antiangiogenic agents plus immune checkpoint inhibitors have recently demonstrated clinical efficacy in advanced renal cell carcinoma (RCC). This commentary summarizes the clinical advances and reviews the potential implications for RCC and other advanced solid tumors. [ABSTRACT FROM AUTHOR]