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Aging is associated with the onset and progression of multiple diseases, which limit health span. Chronic low-grade inflammation in the absence of overt infection is considered the simmering source that triggers age-associated diseases. Failure of many cellular processes during aging is mechanistically linked to inflammation; however, the overall decline in the cellular homeostasis mechanism of autophagy has emerged as one of the top and significant inducers of inflammation during aging, frequently known as inflammaging. Thus, physiological or pharmacological interventions aimed at improving autophagy are considered geroprotective. Rapamycin analogs (rapalogs) are known for their ability to inhibit mTOR and thus regulate autophagy. This study assessed the efficacy of everolimus, a rapalog, in regulating inflammatory cytokine production in T cells from older adults. CD4+ T cells from older adults were treated with a physiological dose of everolimus (0.01 µM), and indices of autophagy and inflammation were assessed to gain a mechanistic understanding of the effect of everolimus on inflammation. Everolimus (Ever) upregulated autophagy and broadly alleviated inflammatory cytokines produced by multiple T cell subsets. Everolimus's ability to alleviate the cytokines produced by Th17 subsets of T cells, such as IL-17A and IL-17F, was dependent on autophagy and antioxidant signaling pathways. Repurposing the antineoplastic drug everolimus for curbing inflammaging is promising, given the drug's ability to restore multiple cellular homeostasis mechanisms. Everolimus inhibits mTORC1 and promotes autophagy in CD4 + T cells from O adults, which induces the activation and translocation of NRF2 to the nucleus. NRF2 induces the production of first-line antioxidant enzymes SOD1, SOD2, and catalase, thus lowering reactive oxygen species and proinflammatory cytokine production [ABSTRACT FROM AUTHOR]

Coccomyxa subellipsoidea KJ (C-KJ) is a green alga with unique immunoregulatory characteristics. Here, we investigated the mechanism underlying the modification of T cell function by C-KJ components. The water-soluble extract of C-KJ was fractionated into protein (P) and sugar (S) fractions acidic (AS), basic (BS), and neutral (NS). These fractions were used for the treatment of peripheral blood mononuclear cells stimulated with toxic shock syndrome toxin-1. Transcriptome analysis revealed that both P and AS enhanced the expression of the genes encoding metallothionein (MT) family proteins, inflammatory factors, and T helper (Th) 17 cytokine and suppressed that of those encoding Th2 cytokines in stimulated T cells. The kinetics of MT1 and MT2A gene expression showed a transient increase in MT1 and maintenance of MT2A mRNA after T cell stimulation in the presence of AS. The kinetics of Th17-related cytokine secretion in the early period were comparable to those of MT2A mRNA. Furthermore, our findings revealed that static, a STAT-3 inhibitor, significantly suppressed MT2A gene expression. These findings suggest that the expression of MTs is involved in the immune regulatory function of C-KJ components, which is partially regulated by Th17 responses, and may help develop innovative immunoregulatory drugs or functional foods. [ABSTRACT FROM AUTHOR]

Aging promotes numerous intracellular changes in T cells that impact their effector function. Our data show that aging promotes an increase in the localization of STAT3 to the mitochondria (mitoSTAT3), which promotes changes in mitochondrial dynamics and function and T‐cell cytokine production. Mechanistically, mitoSTAT3 increased the activity of aging T‐cell mitochondria by increasing complex II. Limiting mitoSTAT3 using a mitochondria‐targeted STAT3 inhibitor, Mtcur‐1 lowered complex II activity, prevented age‐induced changes in mitochondrial dynamics and function, and reduced Th17 inflammation. Exogenous expression of a constitutively phosphorylated form of STAT3 in T cells from young adults mimicked changes in mitochondrial dynamics and function in T cells from older adults and partially recapitulated aging‐related cytokine profiles. Our data show the mechanistic link among mitoSTAT3, mitochondrial dynamics, function, and T‐cell cytokine production. [ABSTRACT FROM AUTHOR]

Coccomyxa subellipsoidea KJ (C-KJ) is a green alga with unique immunoregulatory characteristics. Here, we investigated the mechanism underlying the modification of T cell function by C-KJ components. The water-soluble extract of C-KJ was fractionated into protein (P) and sugar (S) fractions acidic (AS), basic (BS), and neutral (NS). These fractions were used for the treatment of peripheral blood mononuclear cells stimulated with toxic shock syndrome toxin-1. Transcriptome analysis revealed that both P and AS enhanced the expression of the genes encoding metallothionein (MT) family proteins, inflammatory factors, and T helper (Th) 17 cytokine and suppressed that of those encoding Th2 cytokines in stimulated T cells. The kinetics of MT1 and MT2A gene expression showed a transient increase in MT1 and maintenance of MT2A mRNA after T cell stimulation in the presence of AS. The kinetics of Th17-related cytokine secretion in the early period were comparable to those of MT2A mRNA. Furthermore, our findings revealed that static, a STAT-3 inhibitor, significantly suppressed MT2A gene expression. These findings suggest that the expression of MTs is involved in the immune regulatory function of C-KJ components, which is partially regulated by Th17 responses, and may help develop innovative immunoregulatory drugs or functional foods.

Asthma is a global and increasingly prevalent disease. According to the World Health Organization, approximately 235 million people suffer from asthma. Studies suggest that fine particulate matter (PM2.5) can induce innate immune responses, promote allergic sensitization, and exacerbate asthmatic symptoms and airway hyper-responsiveness. Recently, severe asthma and allergic sensitization have been associated with T-helper cell type 17 (TH17) activation. Few studies have investigated the links between PM2.5 exposure, allergic sensitization, asthma, and TH17 activation. This study aimed to determine whether (1) low-dose extracts of PM2.5 from California (PMCA) or China (PMCH) enhance allergic sensitization in mice following exposure to house dust mite (HDM) allergen; (2) eosinophilic or neutrophilic inflammatory responses result from PM and HDM exposure; and (3) TH17-associated cytokines are increased in the lung following exposure to PM and/or HDM. Ten-week-old male BALB/c mice (n = 6-10/group) were intranasally instilled with phosphate-buffered saline (PBS), PM+PBS, HDM, or PM+HDM, on days 1, 3, and 5 (sensitization experiments), and PBS or HDM on days 12-14 (challenge experiments). Pulmonary function, bronchoalveolar lavage cell differentials, plasma immunoglobulin (Ig) protein levels, and lung tissue pathology, cyto-/chemo-kine proteins, and gene expression were assessed on day 15. Results indicated low-dose PM2.5 extracts can enhance allergic sensitization and TH17-associated responses. Although PMCA+HDM significantly decreased pulmonary function, and significantly increased neutrophils, Igs, and TH17-related protein and gene levels compared with HDM, there were no significant differences between HDM and PMCH+HDM treatments. This may result from greater copper and oxidized organic content in PMCA versus PMCH.

Background: IL-17 is reported to be associated with the pathophysiology of Orthodontic Tooth Movement (OTM) by affecting osteoclastogenesis. Objectives: To explore the changes of Th17 cytokines (IL-17, IL-23, and IL-27) expression and its correlation with receptor activator of nuclear factor kappa B ligand (RANKL) during orthodontic tooth movement. Methods: Thirty patients who needed extraction of the first premolar during orthodontic treatment were included. The gingival crevicular fluid was sampled at the day of application (T0), one hour (T1), 24 hours (T2), one week (T3), four weeks (T4), and 12 weeks (T5) after the application of orthodontic force. The expression of Th17 cytokines and RANKL were measured by using enzyme-linked immunosorbent assay and, their correlations were assessed. Results:The levels of IL-17A, IL-17F, IL-23, and IL-27 at both tension and pressure sides of studied teeth at T2-T4 were significantly higher compared with that of T0 and T1. Moreover, the expression of IL-27 at both tension and pressure sides of studied teeth at T2-T4 was significantly lower compared with that of T0 and T1. At T5, IL-17A, IL-17F, IL-23, and IL-27 returned to the baseline level. For the control group, the cytokines were notsignificantly different at various time points. The expression of IL-17A, IL-17F, and IL-23 was positively correlated with RANKL expression at T2-T4, whereas the IL-27 was negatively correlated with RANKL expression at T2-T4. Conclusions: This study provided preliminary evidence that Th17 cytokines may be involved in the regulation of OTM.

Yan Yu,1,* Lili Zhao,1,* Yu Xie,1 Yu Xu,1 Weike Jiao,2 Jianhui Wu,2 Xinyu Deng,2 Guiju Fang,2 Qing Xue,2 Yali Zheng,1,3 Zhancheng Gao1,3 1Department of Respiratory and Critical Care Medicine, Peking University People’s Hospital, Beijing 100044, People’s Republic of China; 2Department of Pulmonary and Critical Care Medicine, Ningde Municipal Hospital Affiliated to Fujian Medical University, Ningde, Fujian 352100, People’s Republic of China; 3Department of Respiratory and Critical Care Medicine, Xiang’An Hospital of Xiamen University, Xiamen, Fujian 361100, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhancheng Gao; Yali Zheng Tel +86 18810900430; Tel +86 15011451515Email zcgao@bjmu.edu.cn; yali_zheng@126.comBackground: T helper (Th) cell cytokine imbalances have been associated with the pathophysiology of chronic obstructive pulmonary disease (COPD), including the Th1/Th2 and Th17/T regulatory cells (Treg) paradigms. Clarifying cytokine profiles during COPD acute exacerbation (AE) and their relationships with clinical manifestations would help in understanding the pathogenesis of disease and improve clinical management.Materials and Methods: Eighty seven patients admitted to the hospital with AEs of COPD were included in this study, and follow-up was conducted after discharge (every 30 days, for a total of 120 days). Sputum samples of patients at different time points (including at admission, discharge, and follow-up) were collected, and sputum cytokine profiling (12 cytokines in total) was performed using a Luminex assay.Results: According to the cytokine profiles at admission, patients were divided into three clusters by a k-means clustering algorithm, namely, Th1high Th17high (n=26), Th1lowTh17low (n=56), and Th1high Th17low (n=5), which revealed distinct clinical characteristics. Patients with Th1high Th17low profile had a significantly longer length of non-invasive ventilation time and length of hospital stay than patients with Th1high Th17high profile (7 vs 0 days, 22 vs 11 days, respectively, p < 0.05), and had the highest AE frequency. Sputum levels of Th17 cytokines (IL-17A, IL-22, and IL-23) during AE were negatively correlated with AE frequency in the last 12 months (r = − 0.258, − 0.289 and − 0.216, respectively, p < 0.05). Moreover, decreased sputum IL-17A levels were independently associated with increased AE frequency, with an OR (95% CI) of 0.975 (0.958– 0.993) and p = 0.006.Conclusion: Th1/Th17 imbalance during AE is associated with the severity of COPD. Decreased Th17 cytokine expression is correlated with increased AE frequency. The Th1/Th17 balance may be a specific target for the therapeutic manipulation of COPD.Keywords: chronic obstructive pulmonary disease, acute exacerbation, Th1 cytokines, Th17 cytokines, therapeutic

Abstract Background Recent studies show that innate lymphoid cells (ILCs) contribute to the development of chronic inflammation and autoimmune disease. In this study, we assessed the ILC function in the development of rheumatoid arthritis (RA). Methods In a mouse model of collagen-induced arthritis (CIA), we identified and purified the ILC subsets in peripheral blood (PB), local lymph nodes (LNs), and joints by fluorescence-activated cell sorting and used quantitative PCR to assess the expression levels of representative cytokines. We also correlated the frequencies of each ILC subset in synovial fluid (SF) with clinical parameters in RA patients. Results In the CIA model, the proportion of CCR6+ ILC3s to total ILCs in joints with active inflammation significantly increased relative to non-arthritic joints (median 29.6% vs 16.7%, p = 0.035). CCR6+ ILC3s from mice with arthritis expressed significantly higher levels of IL-17A and IL-22 mRNA than did comparable cells from control mice (p

Abstract Allergic rhinitis (AR) is an allergic nasal disease characterized by nasal obstruction, rhinorrhea, sneezing, and itching. Type 1 helper T cells (Th1)/type 2 helper T cells (Th2) imbalance has been identified as an important immunological mechanism of AR. In addition, up-regulation of type 17 helper T cells (Th17) also increase the risk of developing AR. Gallic acid (3, 4, 5-trihydroxybenzoic acid, GA), a polyphenol natural product, is obtained from various herbs, red wine, and green tea. It is known to have diverse biological effects such as anti-oxidation, anti-inflammation, anti-microbial and anti-cancer. In the present study, the effect of GA on airway inflammation and expression of Th1, Th2 and Th17 cytokines in an ovalbumin (OVA)-induced AR mouse model were investigated. GA alleviated the nasal allergic symptoms, reduced the thickness of nasal mucosa, attenuated goblet cell hyperplasia and eosinophil cell infiltration in the nasal mucosa, decreased the levels of interleukin (IL)-4, IL-5, IL-13 and IL-17 in nasal lavage fluid (NALF), and diminished the levels of OVA-specific IgE, OVA-specific IgG1 and OVA-specific IgG2a in serum. However, GA increased the expression of interferon-gamma and IL-12 in NALF. Taken together, it suggests that GA may be used as a therapeutic agent for AR. Highlights • Gallic acid alleviated the nasal allergic symptoms. • Gallic acid ameliorated the inflammation in the mouse nose lamina propria. • Gallic acid diminished the levels of OVA-specific IgE and OVA-specific IgG 1 in serum. • Gallic acid increased IFN-γ and IL-12 expression in NALF. • Gallic acid decreased IL-4, IL-5, IL-13, IL-17 and ROR-γt levels in NALF. [ABSTRACT FROM AUTHOR]

Aging promotes numerous intracellular changes in T cells that impact their effector function. Our data show that aging promotes an increase in the localization of STAT3 to the mitochondria (mitoSTAT3), which promotes changes in mitochondrial dynamics and function and T-cell cytokine production. Mechanistically, mitoSTAT3 increased the activity of aging T-cell mitochondria by increasing complex II. Limiting mitoSTAT3 using a mitochondria-targeted STAT3 inhibitor, Mtcur-1 lowered complex II activity, prevented age-induced changes in mitochondrial dynamics and function, and reduced Th17 inflammation. Exogenous expression of a constitutively phosphorylated form of STAT3 in T cells from young adults mimicked changes in mitochondrial dynamics and function in T cells from older adults and partially recapitulated aging-related cytokine profiles. Our data show the mechanistic link among mitoSTAT3, mitochondrial dynamics, function, and T-cell cytokine production., (© 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Hepatitis C virus (HCV) chronic infection causes severe cellular immune dysfunction. Here, we investigated the production of Th17-associated cytokines by peripheral blood mononuclear cells (PBMCs) of untreated patients with HCV, patients presenting an early virologic response (EVR) after 12 weeks of treatment with interferon-α plus ribavirin with or without HCV protease inhibitors, and patients who were nonresponders to HCV therapy. PBMCs were stimulated with HCV core and nonstructural antigens, and the production of Th17-associated cytokines was measured with a Milliplex MAP immunoassay. Core-stimulated PBMCs from both untreated and nonresponder patients produced interleukin (IL)-17A, and vigorous production of IL-17A in response to NS3 antigen was only verified in the untreated group. Nonresponder patients also produced IL-17F after core antigen stimulation. IL-21 production was unaltered in the three groups of patients, whereas IL-17E and IL-22 were not detected. The production of Th17 cytokines by cells from patients showing an EVR was insignificant. IL-17A and IL-17F levels were not correlated with alanine aminotransferase levels or viremia. However, advanced fibrosis was associated with higher IL-17A production in T0 cells stimulated with core antigen. Untreated patients with HCV and patients who were nonresponders to antiviral treatment differed in their PBMC immune responses of Th17-associated cytokines. The early virological response to antiviral treatment dramatically decreased Th17 immune responses to HCV antigens. [ABSTRACT FROM AUTHOR]

Objective This study is to investigate the immunomodulatory effects of the herbal formula of astragalus polysaccharide (APS) and polysaccharopeptide (PSP) in mouse models of immunosuppression and lung cancer. Methods Immune parameters were recorded for these model mice. Peripheral white blood cells (WBC) were detected with the automatic blood cell analyzer. Spleen and thymus indices, and tumor inhibition ratio were obtained. Percentage of peripheral blood CD4 + and CD8 + T lymphocytes were detected by flow cytometry. Serum levels of Th1 (IL-2, TNF, and IFN-γ), Th2 (IL-4, IL-6, and IL-10), and Th17 (IL-17A) were detected with the BD cytometric bead array (CBA) mouseTh1/Th2/Th17 cytokine kit. Results Compared with the NS group, the PSP and APS herbal formula significantly improved the WBC, thymus index, spleen index, CD4 + /CD8 + ratio, TNF, IFN-γ, IL-2, andIL-17Ainimmunosuppressivemice and lung cancer mice ( P < 0. 05). On the contrary, IL-10 was relatively low in the PSP + APS herbal formula group ( P < 0. 05). Besides, the PSP + APS herbal formula group induced comparable tumor inhibiting effect with the AMD group (23.3% and 24.1%, respectively). Conclusion The PSP + APS herbal formula have immunomodulatory effects and anti-tumor activity in mice with of lung cancer. [ABSTRACT FROM AUTHOR]

Background: Recent studies have implied a role for Th17 cells in CRS with nasal polyps (CRSwNP) patients. However, the capacity of these cells to produce Th17 cytokines is still unknown. Here we sought to quantify IL-17A, IL-17F, IL-21, and IL-22 cytokines produced by Th17 cells in mucosal tissue and peripheral blood of CRSwNP, CRS without nasal polyps (CRSsNP) and control patients.Methods: Samples were prospectively collected from CRS patients and non-CRS controls. We used flow cytometry to characterize the Th17 cells and their cytokines in sinonasal tissue and peripheral blood.Results: A total of 36 patients were recruited to the study. CRSwNP patients had significantly more tissue IL-17A (9.53 ± 2.71 vs. 1.11 ± 0.43 vs. 0.77 ± 0.07), IL-17F (4.96 ± 1.48 vs. 0.88 ± 0.31 vs. 0.56 ± 0.04), IL-21 (5.55 ± 2.01 vs. 1.60 ± 0.71 vs. 1.53 ± 0.55) and IL-22 (4.73 ± 1.58 vs. 0.70 ± 0.28 vs. 0.88 ± 0.26) producing Th17 cells compared to CRSsNP and control mucosa per mg of tissue, respectively. Allergic CRSwNP patients had decreased numbers of IL-21 producing Th17 cells compared to non-Allergic CRSwNP. (1.69 ± 0.57 vs. 9.41 ± 3.23) per mg of tissue, respectively (Kruskal-Wallis p < 0.05).Conclusion: In summary our study identified increased numbers of IL-17A, IL-17F, IL-21 and IL-22 positive Th17 cells in CRSwNP patient polyps and peripheral blood suggesting an altered activation state of those cells both locally and systemically. Atopic CRSwNP had decreased amounts of tissue Th17 cell derived IL-21 implying a potential protective role for IL-21 in CRSwNP allergic inflammation.

Background: Recent studies have implied a role for Th17 cells in CRS with nasal polyps (CRSwNP) patients. However, the capacity of these cells to produce Th17 cytokines is still unknown. Here we sought to quantify IL-17A, IL-17F, IL-21, and IL-22 cytokines produced by Th17 cells in mucosal tissue and peripheral blood of CRSwNP, CRS without nasal polyps (CRSsNP) and control patients. Methods: Samples were prospectively collected from CRS patients and non-CRS controls. We used flow cytometry to characterize the Th17 cells and their cytokines in sinonasal tissue and peripheral blood. Results: A total of 36 patients were recruited to the study. CRSwNP patients had significantly more tissue IL-17A (9.53 ± 2.71 vs. 1.11 ± 0.43 vs. 0.77 ± 0.07), IL-17F (4.96 ± 1.48 vs. 0.88 ± 0.31 vs. 0.56 ± 0.04), IL-21 (5.55 ± 2.01 vs. 1.60 ± 0.71 vs. 1.53 ± 0.55) and IL-22 (4.73 ± 1.58 vs. 0.70 ± 0.28 vs. 0.88 ± 0.26) producing Th17 cells compared to CRSsNP and control mucosa per mg of tissue, respectively. Allergic CRSwNP patients had decreased numbers of IL-21 producing Th17 cells compared to non-Allergic CRSwNP. (1.69 ± 0.57 vs. 9.41 ± 3.23) per mg of tissue, respectively (Kruskal-Wallis p < 0.05). Conclusion: In summary our study identified increased numbers of IL-17A, IL-17F, IL-21 and IL-22 positive Th17 cells in CRSwNP patient polyps and peripheral blood suggesting an altered activation state of those cells both locally and systemically. Atopic CRSwNP had decreased amounts of tissue Th17 cell derived IL-21 implying a potential protective role for IL-21 in CRSwNP allergic inflammation. [ABSTRACT FROM AUTHOR]

Background & Aims: Recent reports suggest an involvement of Th17 responses in inflammatory and autoimmune reactions in alcoholic liver disease (ALD). Our study aimed to assess serum levels of Th17-interleukins in ALD with regard to the frequency of liver-specific autoantibodies and degree of liver damage. Methods: Ninety-five patients with ALD were enrolled. Serum concentrations of IL-17F, IL-17A, IL-22 were assessed by ELISA. The presence of autoantibodies AMA-M2, SLA/LP, LKM-1, LC1, anti-F-actin, anti-desmin and anti-myosin in serum was assessed by immunoblotting, ANA antibodies were detected by ELISA. The results were analysed with regard to the degree of hepatic damage. Results: Serum IL-17F was significantly elevated in ALD patients compared to controls (p=0.03). There was a correlation between serum IL-17F and degree of liver failure evaluated by the MELD score (rs=0.23, p=0.03). Serum IL-22 also correlated with MELD score (rs=0.32, p=0.007) and CTP score (rs=0.28, p=0.02). Anti-Factin antibodies were present in 19% and ANA-antibodies in 11% of the patients in the study group, and in no subjects in the control group. The prevalence of anti-F-actin autoantibodies was higher in subjects with more advanced liver diseases but also independently associated with IL-17A in the regression analysis. Furthermore, serum IL-22 in anti-F-actin(+)-patients was significantly higher compared to anti-F-actin(-)-patients (p=0.03). Conclusions: Elevation of serum IL-17A, IL-17F, IL-22 correlated with the progression of liver damage and also with presence of F-actin in ALD. Alcoholic liver disease may trigger autoimmunity and formation of autoantibodies, especially anti-F-actin, with possible engagement of Th17-related cytokines in this process. [ABSTRACT FROM AUTHOR]

The role of T helper-17 (Th17) lymphocytes in the regulation of Schistosoma mansoni soluble egg antigen ( SEA)-induced granuloma is unknown. This study examined the effect of Th17 cytokines ( IL-17 and IL-22) on granulocyte recruitment and functions during SEA-induced granuloma formation in vitro in Schistosoma-infected and noninfected individuals. Granulocytes were isolated from 27 Schistosoma-infected patients and 13 controls and were used for granuloma induction using SEA-conjugated polyacrylamide beads in the presence of Th17 cytokines. Granuloma index was assessed, and granulocyte mediators such as tumour necrosis factor ( TNF-α), hydrogen peroxide (H2O2) and nitric oxide ( NO) were measured in the culture supernatant at the 7th day using enzyme-linked immunosorbent assay ( ELISA). Schistosoma-infected patients had significant larger SEA-induced granuloma than controls. IL-17 (125 pg/mL) induced the optimum size for granuloma within 3-7 days. However, IL-22 at different concentrations up to 300 pg/mL had no effect on granuloma formation. Using both cytokines simultaneously, IL-22 suppressed the effect of IL-17 and prevented granuloma formation. IL-17 significantly decreased TNF-α, H2O2 and NO levels in Schistosoma-infected individuals. In contrast, IL-22 increased TNF-α and H2O2 levels. In conclusion, IL-17 accelerates SEA-induced granuloma formation and inhibits granulocytes functions in Schistosoma-infected patients, while IL-22 inhibited the granuloma formation, but enhanced granulocyte functions. [ABSTRACT FROM AUTHOR]

Agonistic anti-4-1BB antibodies (Abs) play a central role in immunomodulatory conditions that control the pathogenesis of immune-mediated autoimmune and allergic diseases. However, the effects of agonistic anti-4-1BB Abs have not been examined in an experimental mouse model of psoriasis. Therefore, we investigated the protective effects of agonistic anti-4-1BB Abs, using imiquimod (IMQ)-induced psoriasis-like dermatitis in mice, a condition histologically and clinically similar to human psoriasis. We found that administration of agonistic anti-4-1BB Abs (10 mg/kg) significantly alleviated the severity of IMQ-induced psoriasis-like skin inflammation in mice, with reduced histologic symptoms, including inflammatory infiltration, parakeratosis, and hyperkeratosis. Subsequent analyses revealed that the production of Th17 cytokines (IL-17A and IL-23) in the serum and skin of IMQ-induced mice was significantly inhibited by agonistic anti-4-1BB Abs (10 mg/kg), although Th1 cytokines (TNF-α and IFN-γ) were not. Moreover, administration of agonistic anti-4-1BB Abs (10 mg/kg) induced a relative increase of CD4 + FoxP3 + regulatory T (Treg) cells in the spleen and draining lymph node (DLN). Taken together, our data provide evidence that agonistic anti-4-1BB Abs possesses immunosuppressive properties in IMQ-induced psoriasis-like skin inflammation, providing insight into the immunomodulatory effect of agonistic anti-4-1BB Abs for psoriasis immunotherapy. [ABSTRACT FROM AUTHOR]

Appropriate immune responses and mucosal barrier functions are required for the maintenance of intestinal homeostasis. Defects in this defense system may lead to inflammatory disorders such as inflammatory bowel disease. Downstream of tyrosine kinases 1 (Dok-1) and its closest homolog, Dok-2, are preferentially expressed in immune cells, and play essential roles in the negative regulation of multiple signaling pathways in both innate and adaptive immunity. However, the function of these proteins in intestinal homeostasis remained unclear. Here we show that Dok-1/-2 double knockout (DKO) mice were highly susceptible to dextran sodium sulfate (DSS)-induced colitis compared with Dok-1 or Dok-2 single KO and wild type (WT) mice. Furthermore, DSS-treated Dok-1/-2 DKO mice exhibited increased colonic tissue damage accompanied by reduced proliferation of the epithelial cells relative to WT controls, suggesting that Dok-1/-2 DKO mice have defects in the repair of intestinal epithelial lesions. In addition, the levels of the Th17 cytokines IL-17A and IL-22, which have protective roles in DSS-induced colitis, were reduced in DSS-treated Dok-1/-2 DKO mice compared with WT mice. Taken together, our results demonstrate that Dok-1 and Dok-2 negatively regulate intestinal inflammation, apparently through the induction of IL-17A and IL-22 expression. [ABSTRACT FROM AUTHOR]

Background: Chronic obstructive pulmonary disease (COPD) is associated with chronic inflammation and impaired immune response to pathogens leading to bacteria-induced exacerbation of the disease. A defect in Th17 cytokines in response to Streptococcus pneumoniae, a bacteria associated with COPD exacerbations, has been recently reported. Dendritic cells (DC) are professional antigen presenting cells that drive T-cells differentiation and activation. In this study, we hypothesized that exposure to cigarette smoke, the main risk factor of COPD, might altered the pro-Th17 response to S. pneumoniae in COPD patients and human DC.Methods: Pro-Th1 and -Th17 cytokine production by peripheral blood mononuclear cells (PBMC) from COPD patients was analyzed and compared to those from smokers and non-smokers healthy subjects. The effect of cigarette smoke extract (CSE) was analyzed on human monocyte-derived DC (MDDC) from controls exposed or not to S. pneumoniae. Bacteria endocytosis, maturation of MDDC and secretion of cytokines were assessed by flow cytometry and ELISA, respectively. Implication of the oxidative stress was analyzed by addition of antioxidants and mitochondria inhibitors. In parallel, MDDC were cocultured with autologous T-cells to analyze the consequence on Th1 and Th17 cytokine production.Results: PBMC from COPD patients exhibited defective production of IL-1β, IL-6, IL-12 and IL-23 to S. pneumoniae compared to healthy subjects and smokers. CSE significantly reduced S. pneumoniae-induced MDDC maturation, secretion of pro-Th1 and -Th17 cytokines and activation of Th1 and Th17 T-cell responses. CSE exposure was also associated with sustained CXCL8 secretion, bacteria endocytosis and mitochondrial oxidative stress. Antioxidants did not reverse these effects. Inhibitors of mitochondrial electron transport chain partly reproduced inhibition of S. pneumoniae-induced MDDC maturation but had no effect on cytokine secretion and T cell activation.Conclusions: We observed a defective pro-Th1 and -Th17 response to bacteria in COPD patients. CSE exposure was associated with an inhibition of DC capacity to activate antigen specific T-cell response, an effect that seems to be not only related to oxidative stress. These results suggest that new therapeutics boosting this response in DC may be helpful to improve treatment of COPD exacerbations. [ABSTRACT FROM AUTHOR]

The Th1 cytokines production associated to signal transducer and activator of transcription 4 (STAT4) signaling amplifies the pro-inflammatory response in acute respiratory distress syndrome (ARDS). The anti-inflammatory action of commensal bacteria has been described as a secondary effect dependent on IL-10- secreting Treg cells that can act in organs far from the gut, including the lung. Despite it, no data is showing whether the previous reported anti-inflammatory action of probiotics is associated with its immunomodulatory effect dependent on Treg cells in a murine model of ARDS. Therefore, herein we focused on the short-term pretreatment effect with Lacticaseibacillus rhamnosus (Lr) in STAT4-associated Th1 cytokines as well as in population of IL-10- secreting Treg cells in a murine model of ARDS. Assays were performed in experimental groups divided into control, LPS, and Lr + LPS. Total and differential cells from bronchoalveolar lavage fluid (BALF) were counted through microscopy and the IL-10, IL-12, IL-17, IL-18, IL-22, IL-23, IL-27, IFN-γ, MMP-9, and TIMP were measured by ELISA. The peribronchial neutrophils were assessed using morphometry and for pulmonary edema was measured by Evans blue dye extravasation. The gene expression for STAT4, T-bet, STAT3, RORɣt, STAT5, and Foxp3 were measured by Real-Time PCR. Population of IL-10-secreting Treg cells was performed by flow cytometer. Data showed that pretreatment with Lr attenuated the number of inflammatory cells, secretion of both Th1 and Th17 cytokines, expression of STAT4/T-bet and STAT3/RORɣt in lung as well as alterations in lung morphometry. Otherwise, Lr was not efficient to restore mRNA expression for STAT5 and Foxp3 expression and population of IL-10-secreting Treg cells. Thus, beneficial effect of short-term pretreatment with Lr in murine model of ARDS is not dependent on an increased immunomodulatory action of IL-10-secreting Treg cells, however the anti-inflammatory effect of Lr has as target the Th1 and Th17 cytokines as well as signaling involving the STAT4/T-bet and STAT3/RORɣt. Our findings show new data highlighting that the anti-inflammatory effect of short-term pretreatment with Lr on acute lung inflammation in a murine model of ARDS targets Th1 cytokines associated with STAT4/T-bet signaling as well as the Th17 cytokines associated with STAT3/RORɣt signaling, without interfering with anti-inflammatory signaling of STAT5/Foxp3/IL-10. [Display omitted] • Lr protects against the lung inflammatory insult. • Lr attenuates the airway resistance. • Lr reduces Th1 cytokine and downregulates STAT4/T-bet signaling. • Lr reduced Th17 cytokines and downregulates STAT3/RORɣt. • STAT5/Foxp3/IL-10 signaling is not targeted by the anti-inflammatory effect of Lr. [ABSTRACT FROM AUTHOR]

The characterization of host immune responses to human immunodeficiency virus (HIV) in HIV controllers and individuals with high exposure but seronegativity to HIV (HESN) is needed to guide the development of effective preventive and therapeutic vaccine candidates. However, several technical hurdles severely limit the definition of an effective virus-specific T-cell response. By using a toggle-peptide approach, which takes HIV sequence diversity into account, and a novel, boosted cytokine staining/flow cytometry strategy, we here describe new patterns of T-cell responses to HIV that would be missed by standard assays. Importantly, this approach also allows detection of broad and strong virus-specific T-cell responses in HESN individuals that are characterized by a T-helper type 1 cytokine–like effector profile and produce cytokines that have been associated with potential control of HIV infection, including interleukin 10, interleukin 13, and interleukin 22. These results establish a novel approach to improve the current understanding of HIV-specific T-cell immunity and identify cellular immune responses and individual cytokines as potential markers of relative HIV resistance. As such, the findings also help develop similar strategies for more-comprehensive assessments of host immune responses to other human infections and immune-mediated disorders. [ABSTRACT FROM AUTHOR]

We evaluated the potential relationship between miRNAs and Th17 cytokines in multiple myeloma (MM) patients. Twenty-seven newly diagnosed myeloma patients and eight normal donors were studied. We determined that the relative expression levels of miR-15a/16, miR-34a, miR-194 in MM patients were significantly lower than those in the healthy controls with exception for miR-181a/b, which showed significantly higher in MM patients ( P < 0.05). In contrast, the levels of IL-17, IL-21 and IL-27 were up-regulated in MM patients compared to healthy controls while IL-22 was down-regulated ( P < 0.05). The expression patterns of them were differentially present in various groups according to the International Staging System (ISS) criteria. Up-regulated IL-17, IL-21 and IL-27 may potentially down-regulate the expression of several miRNAs in MM patients. Establishment of the relationship may be useful for understanding the pathogenesis of MM and for clinical diagnosis of the disease. [ABSTRACT FROM AUTHOR]

Highlights: [•] We examine modulation by LL-37 of cytokine/dsRNA-induced keratinocyte response. [•] LL-37 upregulates cytokine (IL-17A/IL-22/TNF-α/IFN-γ)-induced CXCL8 and/or IL-6. [•] LL-37 suppresses cytokine (TNF-α/IFN-γ)-induced CXCL10 and/or CCL5. [•] LL-37 suppresses dsRNA-induced CXCL8, CXCL10, CCL5, and TSLP. [•] The results suggest more involvement of LL-37 than expected in skin inflammations. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate and characterize the therapeutic potential of curdlan, a naturally occurring β-glucan immunomodulator, against visceral leishmaniasis, a fatal parasitic disease. Curdlan eliminated the liver and spleen parasite burden in a 45-day BALB/c mouse model of visceral leishmaniasis at a dosage of 10 mg/kg/day as determined by Giemsa-stained organ impression smears. Curdlan was associated with production of the disease-resolving T-helper (Th) 1 and Th17-inducing cytokines interleukin (IL)-6, IL-1β, and IL-23, as well as with production of Th17 cytokines IL-17 and IL-22, as determined by enzyme-linked immunosorbent assay (ELISA) and real time polymerase chain reaction (RT-PCR). Reversal of curdlan-mediated protection by anti-IL-17 and anti-IL-23 monoclonal antibodies showed the importance of Th17 cytokines. Significantly decreased production of both IL-17 and IL-22 by mice that received anti-IL-23 antibody suggested the essential role of IL-23 in Th17 differentiation. Although administration of recombinant IL-17 or IL-23 caused significant suppression of the organ parasite burden, with marked generation of interferon γ and nitric oxide (NO), effects were much faster for IL-17. These results documented that although both IL-23 and IL-17 play major roles in the antileishmanial effect of curdlan, the effect of IL-23 may occur indirectly, through the induction of IL-17 production. [ABSTRACT FROM AUTHOR]

Background: Subepithelial fibrosis is one of the most critical structural changes affecting bronchial airway function during asthma. Eosinophils have been shown to contribute to the production of pro-fibrotic cytokines, TGF-β and IL-11, however, the mechanism regulating this process is not fully understood. Objective: In this report, we investigated whether cytokines associated with inflammation during asthma may induce eosinophils to produce pro-fibrotic cytokines. Methods: Eosinophils were isolated from peripheral blood of 10 asthmatics and 10 normal control subjects. Eosinophils were stimulated with Th1, Th2 and Th17 cytokines and the production of TGF-β and IL-11 was determined using real time PCR and ELISA assays. Results: The basal expression levels of eosinophil derived TGF-β and IL-11 cytokines were comparable between asthmatic and healthy individuals. Stimulating eosinophils with Th1 and Th2 cytokines did not induce expression of pro-fibrotic cytokines. However, stimulating eosinophils with Th17 cytokines resulted in the enhancement of TGF-β and IL-11 expression in asthmatic but not healthy individuals. This effect of IL-17 on eosinophils was dependent on p38 MAPK activation as inhibiting the phosphorylation of p38 MAPK, but not other kinases, inhibited IL-17 induced pro-fibrotic cytokine release. Conclusions: Th17 cytokines might contribute to airway fibrosis during asthma by enhancing production of eosinophil derived pro-fibrotic cytokines. Preventing the release of pro-fibrotic cytokines by blocking the effect of Th17 cytokines on eosinophils may prove to be beneficial in controlling fibrosis for disorders with IL-17 driven inflammation such as allergic and autoimmune diseases. [ABSTRACT FROM AUTHOR]

Background: Recent studies point to important roles for IL-17 and Th17 cells in sustaining chronic inflammation and articular destruction in rheumatoid arthritis (RA). We investigated the effects of TNF inhibitor on innate inflammatory and Th17 cytokines production by ex vivo lipopolysaccharide (LPS)-stimulated whole blood in patients with RA and the associations of cytokine levels in whole blood cultures with autoantibodies and markers of disease activity. Materials and methods: Whole blood cultures from 18 healthy volunteers and 19 RA patients on etanercept therapy were stimulated with LPS and the production of IL-6, TNF-α, IL-23, IL-17A and IL-21 was measured by ELISA. Results: After stimulation with LPS, the interleukin (IL)-17A ( p = 0.020) and IL-21 ( p = 0.0001) secretions were significantly higher in patients with RA than in controls, while the TNF-α ( p = 0.002) was significantly lower at baseline. Etanercept significantly decreased IL-21 production ( p = 0.007), while IL-6 production ( p = 0.005) significantly increased after 6 months of therapy. IL-21 significantly correlated with RF ( r = 0.917, p < 0.01) and antimutated citrullinated vimentin antibodies ( r = 0.770, p < 0.01) at baseline. Logistic regression analysis revealed that baseline IL-21 levels ( p = 0.004) were significant predictors of DAS28-ESR at 6 months follow-up. Discussion: Stimulation with LPS increased production of Th17 cytokines in whole blood cultures in patients with RA. Etanercept therapy decreased IL-21 secretion, while the capacity of whole blood cells to produce IL-6 increased. IL-21 production is strongly associated with the levels of autoantibodies. Our findings suggest that IL-21 production in LPS-stimulated whole blood cultures may be predictive of clinical response to etanercept treatment in patients with RA. [ABSTRACT FROM AUTHOR]

Adaptive immunity has long been regarded as the major player in protection against most fungal infections. Mounting evidence suggest however, that both innate and adaptive responses intricately collaborate to produce effective antifungal protection. Dendritic cells (DCs) play an important role in initiating and orchestrating antifungal immunity; neutrophils, macrophages and other phagocytes also participate in recognising and eliminating fungal pathogens. Adaptive immunity provides a wide range of effector and regulatory responses against fungal infections. Th1 responses protect against most forms of mycoses but they associate with significant inflammation and limited pathogen persistence. By contrast, Th2 responses enhance persistence of and tolerance to fungal infections thus permitting the generation of long-lasting immunological memory. Although the role of Th17 cytokines in fungal immunity is not fully understood, they can enhance proinflammatory or anti-inflammatory responses or play a regulatory role in fungal immunity all depending on the pathogen, site/phase of infection and host immunostatus. T regulatory cells balance the activities of various Th cell subsets thereby permitting inflammation and protection on the one hand and allowing for tolerance and memory on the other. Here, recent developments in fungal immunity research are reviewed as means of tracing the emergence of a refined paradigm where innate and adaptive responses are viewed in the same light. [ABSTRACT FROM AUTHOR]