Pathological role of interleukin-17 in poly I:C-induced hepatitis.
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ABSTRACT:
SUBMITTER: He J
PROVIDER: S-EPMC3777971 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:UnlabelledIt is well established that interleukin (IL)-22 has hepatoprotective and antifibrotic functions in acute liver injury models; however, its function in patients with liver fibrosis and liver cirrhosis (LC) remains obscure. In the current study, we demonstrated that expression of numerous IL-22 pathway-associated genes was significantly up-regulated in hepatitis B virus (HBV)-infected liver tissues, compared to normal controls, through microarray analysis. In agreement with these findings, liver-infiltrating IL-22(+) cells were largely increased in HBV-infected patients with LC, compared to those without LC or healthy subjects, and were positively associated with liver fibrosis staging scores. Immunohistochemistry and flow cytometric analyses revealed that IL-22 was produced by multiple intrahepatic immune cells and, preferentially, by T-helper (Th) 17 cells in LC patients. In an HBV transgenic (Tg) mouse model of T-cell-mediated chronic liver inflammation and fibrosis, blockade of IL-22 attenuated hepatic expression of chemokine (C-X-C motif) ligand 10 and chemokine (C-C motif) ligand 20 (CCL20) and subsequently reduced Th17 recruitment and liver inflammation and fibrosis progression. In vitro treatment with IL-22 stimulated hepatic stellate cells (HSCs) to secrete several chemokines and subsequently promoted Th17 cell chemotaxis. Blocking C-X-C chemokine receptor type 3 or CCL20 reduced Th17 cell chemotaxis by IL-22-treated HSCs.ConclusionsIL-22 plays a pathological role in exacerbating chronic liver inflammation and fibrosis by recruiting hepatic Th17 cells in HBV-infected patients and HBV Tg mice.
| S-EPMC3970185 | biostudies-literature
Project description:BackgroundAlthough autophagy is an essential cellular salvage process to maintain cellular homeostasis, pathological autophagy can lead to cardiac abnormalities and ultimately heart failure. Therefore, a tight regulation of autophagic process would be important to treat chronic heart failure. Previously, we have shown that IL-10 strongly inhibited pressure overload-induced hypertrophy and heart failure, but role of IL-10 in regulation of pathological autophagy is unknown. Here we tested the hypothesis that IL-10 inhibits angiotensin II-induced pathological autophagy and this process, in part, leads to improve cardiac function.Methods and resultsChronic Ang II strongly induced mortality, cardiac dysfunction in IL-10 Knockout mice. IL-10 deletion exaggerated pathological autophagy in response to Ang II treatment. In isolated cardiac myocytes, IL-10 attenuated Ang II-induced pathological autophagy and activated Akt/mTORC1 signaling. Pharmacological or molecular inhibition of Akt and mTORC1 signaling attenuated IL-10 effects on Ang II-induced pathological autophagy. Furthermore, lysosomal inhibition in autophagic flux experiments further confirmed that IL-10 inhibits pathological autophagy via mTORC1 signaling.ConclusionOur data demonstrate a novel role of IL-10 in regulation of pathological autophagy; thus can act as a potential therapeutic molecule for treatment of chronic heart disease.
| S-EPMC4689660 | biostudies-literature
Project description:The specific contribution of interleukin-17/interleukin-17 receptor (IL-17/IL-17R)-mediated responses in regulating host susceptibility against obligatory intracellular Chlamydia infection was investigated in C57BL/6 and C3H/HeN mice during Chlamydia muridarum respiratory infection. We demonstrated that Chlamydia stimulated IL-17/IL-17R-associated responses in both Chlamydia-resistant C57BL/6 and Chlamydia-susceptible C3H/HeN mice. However, C3H/HeN mice developed a significantly greater IL-17/IL-17R-associated response than C57BL/6 mice did. This was reflected by an increase in IL-17 mRNA expression, a higher recall IL-17 production from splenocytes upon antigen restimulation, and higher production of Th17-related cytokines (IL-23 and IL-6) and chemokines (chemokine [C-X-C motif] ligand 2 [CXCL1]/keratinocyte-derived chemokine [KC] and CXCL2/macrophage inflammatory protein 1 [MIP2]) in C3H/HeN mice than in C57BL/6 mice. Furthermore, C3H/HeN mice displayed a massive accumulation of activated and preactivated neutrophils in the airway and lung parenchyma compared to their C57BL/6 counterparts. We further demonstrated that the skewed IL-17/Th17 profile in C3H/HeN mice was predisposed by a higher basal level of IL-17 receptor C (IL-17RC) expression and then further amplified by a higher inducible IL-17RA expression in lungs. Most importantly, in vivo delivery of IL-17RA antagonist that resulted in a 50% reduction in the neutrophilic infiltration in lungs was able to reverse the susceptible phenotype of C3H/HeN mice to respiratory Chlamydia infection. Thus, our data for the first time have demonstrated a critical role for the IL-17/IL-17R axis in regulating host susceptibility to Chlamydia infection in mice.
| S-EPMC2772560 | biostudies-literature
Project description:While there now exist effective treatments for type 2 high, eosinophilic asthma, there are no specific therapies for 40-50% of people with asthma with other phenotypes, which result from poorly understood underlying pathological mechanisms. One such pathology is neutrophilic inflammation, which has been associated with interleukin (IL)-17 family cytokines. Human genetic studies identified IL-17 polymorphisms associated with asthma; in murine models of allergic airways disease, IL-17A contributes to airway hyperresponsiveness, and in humans, elevated airway IL-17A levels are repeatedly observed in severe asthma. However, the directionality of this association is unknown, and the assumption that IL-17 cytokines drive disease pathology remains speculative. Here, we explore the evidence underlying the relationship between IL-17 and asthma, we review lessons learned from investigating IL-17 in other inflammatory diseases, and discuss the possibility that IL-17 may even be protective in asthma rather than pathogenic. We also critically examine the newly proposed paradigm of a reciprocal relationship between type 2 and type 17 airways inflammation. In summary, we suggest an association between IL-17 and asthma, but research is needed examining the diverse functions of these cytokines, their longitudinal stability, their response to clinical interventions, and for mechanistic studies determining whether they are protective or pathogenic.
| S-EPMC7248344 | biostudies-literature
Project description:We have shown previously that T cells are required for the full development of angiotensin II-induced hypertension. However, the specific subsets of T cells that are important in this process are unknown. T helper 17 cells represent a novel subset that produces the proinflammatory cytokine interleukin 17 (IL-17). We found that angiotensin II infusion increased IL-17 production from T cells and IL-17 protein in the aortic media. To determine the effect of IL-17 on blood pressure and vascular function, we studied IL-17(-/-) mice. The initial hypertensive response to angiotensin II infusion was similar in IL-17(-/-) and C57BL/6J mice. However, hypertension was not sustained in IL-17(-/-) mice, reaching levels 30-mm Hg lower than in wild-type mice by 4 weeks of angiotensin II infusion. Vessels from IL-17(-/-) mice displayed preserved vascular function, decreased superoxide production, and reduced T-cell infiltration in response to angiotensin II. Gene array analysis of cultured human aortic smooth muscle cells revealed that IL-17, in conjunction with tumor necrosis factor-alpha, modulated expression of >30 genes, including a number of inflammatory cytokines/chemokines. Examination of IL-17 in diabetic humans showed that serum levels of this cytokine were significantly increased in those with hypertension compared with normotensive subjects. We conclude that IL-17 is critical for the maintenance of angiotensin II-induced hypertension and vascular dysfunction and might be a therapeutic target for this widespread disease.
| S-EPMC2819301 | biostudies-literature
Project description:BackgroundImmunological factors play a unique role in the setting of preeclampsia; there is a rising debate about the performance of interleukin 17 (IL-17) as inflammatory mediator in its pathogenesis. The purpose of this paper was to evaluate the significance of IL-17 in the diagnosis and prognosis of preeclampsia and estimate a cutoff value for better prediction.MethodsA prospective case control study, 40 patient were enrolled in the study, two groups were designed: a normotensive (control) group (n=20) and preeclampsia group (n=20). Both groups were compared regarding serum IL-17 level to clarify its significance, then ROC curve analysis was done to establish the best cutoff level to predict preeclampsia, with further assessment of its relation to blood pressure to determine its prognostic value.ResultsWe noted a statistically significant difference in serum IL-17 (pg/mL) level between the preeclampsia and control group (P<0.05). The best cutoff value of serum IL-17 in preeclampsia was (8.2 pg/mL) with a sensitivity of 100%, specificity 80% and accuracy 89%. There was also significant variation in its concentrations before and after control of blood pressure and a significant positive correlation with systolic blood pressure level (r=0.9).ConclusionIL-17 is a significant inflammatory biomarker in preeclampsia with useful prognostic power to predict severity of disease.
| S-EPMC6628960 | biostudies-literature
Project description:With 7.6 million deaths globally, cancer according to the World Health Organisation is still one of the leading causes of death worldwide. Interleukin 17 (IL-17) is a cytokine produced by Th17 cells, a T helper cell subset developed from an activated CD4+ T-cell. Whilst the importance of IL-17 in human autoimmune disease, inflammation, and pathogen defence reactions has already been established, its potential role in cancer progression still needs to be updated. Interestingly studies have demonstrated that IL-17 plays an intricate role in the pathophysiology of cancer, from tumorigenesis, proliferation, angiogenesis, and metastasis, to adapting the tumour in its ability to confer upon itself both immune, and chemotherapy resistance. This review will look into IL-17 and summarise the current information and data on its role in the pathophysiology of cancer as well as its potential application in the overall management of the disease.
| S-EPMC4119694 | biostudies-literature
Project description:Autoimmune hepatitis is an interface hepatitis characterized by the progressive destruction of the liver parenchyma, the cause of which is still obscure. Interleukin (IL)-17A is a major driver of autoimmunity, which can be produced by innate immune cells against several intracellular pathogens. Here, we investigated the involvement of IL-17A in a mice model of immune-mediated hepatitis with the intestine exposed to Salmonella typhimurium. Our results showed more severe Concanavalin (Con) A-induced liver injury and gut microbiome dysbiosis when the mice were treated with a gavage of S. typhimurium. Then the Natural Killer (NK) T cells were over-activated by the accumulated IL-17A in the liver in the Con A and S. typhimurium administration group. IL-17A could activate NKT cells by inducing CD178 expression via IL-4/STAT6 signaling. Furthermore, via the portal tract, the laminae propria mucosal-associated invariant T (MAIT) cell-derived IL-17A could be the original driver of NKT cells’ over-activation in intragastric administration of S. typhimurium and Con A injection. In IL-17A deficient mice, Con A-induced liver injury and NKT cells activation was alleviated. However, when AAV-sh-mIL-17a was used to specifically knock down IL-17A in liver, it seemed that hepatic IL-17a knock down did not significantly influence the liver injury. Our results suggested that, under Con A-induction, laminae propria MAIT-derived IL-17A activated hepatic NKT, and this axis could be a therapeutic target in autoimmune liver disease.
2023-03-01 | GSE199311 | GEO
Project description:The variable efficacy of tuberculosis (TB) vaccines and the emergence of drug-resistant strains of Mycobacterium tuberculosis (Mtb) emphasize the urgency for not only generating new and more effective vaccines against TB but also understanding the underlying mechanisms that mediate vaccine-induced protection. We demonstrate that mucosal adjuvants, such as type II heat labile enterotoxin (LT-IIb), delivered through the mucosal route induce pulmonary Mtb-specific T helper type 17 (Th17) responses and provide vaccine-induced protection against Mtb infection. Importantly, protection is interferon-? (IFN?)-independent but interleukin-17 (IL-17)-dependent. Our data show that IL-17 mediates C-X-C motif chemokine ligand 13 (CXCL13) induction in the lung for strategic localization of proinflammatory cytokine-producing CXCR5+ (C-X-C motif chemokine receptor 5-positive) T cells within lymphoid structures, thereby promoting early and efficient macrophage activation and the control of Mtb. Our studies highlight the potential value of targeting the IL-17-CXCL13 pathway rather than the IFN? pathway as a new strategy to improve mucosal vaccines against TB.
| S-EPMC3732523 | biostudies-literature
Project description:ObjectiveThe aim of this study was to longitudinally evaluate and analyze the role of interleukin-22-producing CD4 positive cells (IL-22) in the pathogenesis of Hepatitis C Virus recurrence after Orthotopic Liver Transplantation (HCV-OLT).Methods15 HCV-OLT, 15 age- and gender- matched non-HCV post-OLT (OLT) and 15 hepatitis C virus infected (HCV) patients were enrolled into our study from the liver transplantation and research center at Beijing 302 Hospital. We determined the frequencies of IL-22 using flow cytometry and expression of IL-22 mRNA using PCR in peripheral blood and liver tissue. We also divided HCV-OLT patients into rapid fibrosis progression (RFP) and slow fibrosis progression (SFP), examined IL-22 cells and analyzed the correlations between IL-22 frequencies and liver injury, fibrosis and clinical parameters. Moreover, we investigated the role of IL-22 in Human Hepatic Stellate Cells (HSCs).ResultsThe levels of serum IL-22, frequencies of IL-22 producing cells in peripheral blood mononuclear cells, and expression of IL-22 mRNA and protein in the liver in the HCV-OLT group were significantly higher than that in the HCV and OLT groups. Furthermore, eight (53.3%) patients developed RFP after two years; another three patients were diagnosed liver cirrhosis. The frequencies of IL-22 were much higher in RFP compared with SFP, while no significant difference existed between OLT and SFP. Intrahepatic IL-22 positive cells were located in fibrotic areas and significantly correlated with α-smooth muscle actin (α-SMA) and fibrosis staging scores, not with grading scores and HCRVNA. In vitro, IL-22 administration prevented HSCs apoptosis, promoted HSCs proliferation and activation, up-regulated the expression of HSC-sourced growth factors including α-SMA, TGF-β and TIMP-1, and increased the production of liver fibrosis markers including laminin, hyaluronic acid and collagen type IV.ConclusionPeripheral and intrahepatic IL-22 is up-regulated and plays a pathological role in exacerbating liver fibrosis by activating HSCs in HCV-OLT patients, which may predict RFP and serve as an attractive target for anti-fibrotic therapy.
| S-EPMC4849629 | biostudies-literature