IL-10 is significantly involved in HSP70-regulation of experimental subretinal fibrosis.
Ontology highlight
ABSTRACT:
SUBMITTER: Yang Y
PROVIDER: S-EPMC3869650 | biostudies-literature | 2013
REPOSITORIES: biostudies-literature
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Project description:Subretinal fibrosis results in local destruction of retinal structures and permanent vision loss, representing the end stage of neovascular age-related macular degeneration (AMD). Histological examination of fibrotic specimens from AMD patients has uncovered a wide range of cellular and acellular components. However, their origins and roles in fibrosis remain largely unexplored. Using a laser-induced photocoagulation model with collagen 1?1-GFP reporter mice, we demonstrate, by cell-lineage tracing, that pericytes associating with choroidal microvasculature are activated upon injury and infiltrate into the subretinal space as significant components of fibrotic lesions. In contrast to their choroidal precursors, infiltrating pericytes acquire stellate-like structures, upregulate expression of fibrogenic molecules and colocalize with extracellular fibrotic scar. Collectively, our results identify the choroidal perivascular niche as a novel source of subretinal fibrosis after photocoagulation, and suggest that collagen 1-expressing pericytes are potential targets for therapeutic intervention to suppress subretinal fibrosis and preserve vision.
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Project description:Surgeries, particularly ileocecal resection (ICR), are often required in the treatment of Crohn's disease (CD). However, recurrences are common for patients who undergo ICR, and anastomotic fibrosis is the main cause of re-operation. The present study aimed to investigate the therapeutic effects of triptolide (TPL) in ameliorating fibrosis following ileocolonic anastomosis. A model of IL‑10‑/‑ mice undergoing ICR was used to study postsurgical inflammation and fibrosis of anastomosis. For this purpsose, interleukin (IL)‑10‑/‑ mice were randomly divided into 3 groups as follows: the control group, the saline‑treated group subjected to ICR (ST‑ICR) and the TPL‑treated group subjected to ICR (TT‑ICR). Wild‑type (WT) mice of matching ages were assigned to the WT group. The effects of TPL treatment on ileocolonic anastomosis were determined by histopathological evaluation, western blot analysis and ELISA. The analysis of the effects of TPL treatment on microRNA‑16‑1 (miR‑16‑1) and heat shock protein 70 (HSP70) expression was carried out by RT‑qPCR and western blot analysis. Compared with the control group, significantly higher inflammation scores following anastomosis were observed in the ST‑ICR group (P<0.05), although reversion was observed in the TT‑ICR group, which was consistent with changes in the area of CD4+ cell infiltration. The elevated fibrosis scores and the overexpression of procollagen I and III in the ST‑ICR group were all inhibited by TPL. With an increase in the severity of inflammation and fibrosis, the levels of IL‑6, tumor necrosis factor‑α (TNF‑α) and transforming growth factor‑β1 (TGF‑β1) increased; however, a significant decrease in these levels was observed following treatment with TPL (P<0.05). The results of RT‑qPCR revealed that the upregulated miR‑16‑1 levels in the ST‑ICR group were significantly reduced by TPL. HSP70, which can be inhibited by miR-16-1, ameliorates anastomotic inflammation and fibrosis. Thus, the present study demonstrates that TPL exerts a protective effect against fibrosis following anastomosis in CD. The miR‑16‑1/HSP70 signaling pathway, which can be regulated by TPL, may thus represent a novel therapeutic option in CD that deserves further investigation.
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Project description:Interleukin-10 (IL-10) and interleukin-27 (IL-27) both exert counterregulatory immunodeactivation in visceral Leishmania donovani infection. We studied experimental L. donovani infection in the livers of IL-10-/- and IL-27Rα-/- mice and observed that in IL-27Rα-/-, but not IL-10-/- mice, interferon-gamma (IFN-γ) and tumor necrosis factor (TNF) were required for heightened granulomatous inflammation and accelerated control of intracellular parasite replication. This difference in mechanism, along with residual IL-10 activity in IL-27Rα-/- mice, suggested targeting IL-27 in addition to IL-10 in a macrophage-activating, anti-counterregulatory cytokine treatment strategy. In C57BL/6 wild-type mice with established liver infection, a single injection of anti-IL-27 p28 or anti-IL-10R monoclonal antibody enhanced granuloma assembly, enabled macrophage activation, and induced comparable parasite killing (49-56%). However, anti-IL-27 p28 plus anti-IL-10R combination treatment did not increase leishmanicidal effects. These results suggest that IL-27 and IL-10 may operate in a linked deactivating mechanism and that in this intracellular infection, either IL-27 or IL-10 is a suitable immunotherapeutic target.
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Project description:IL-10 production by Th17 cells is critical for limiting autoimmunity and inflammatory responses. Gene array analysis on Stat6 and T-bet double deficient Th17 cells identified the Th2 transcription factor c-Maf to be synergistically up-regulated by IL-6 plus TGFbeta, and associated with Th17 IL-10 production. Both c-Maf and IL-10 induction during Th17 polarization depended on Stat3, but not Stat6 or Stat1, and mechanistically differed from IL-10 regulation by Th2 or IL-27 signals. TGFbeta was also synergistic with IL-27 to induce c-Maf, and induced Stat1 independent IL-10 expression in contrast to IL-27 alone. Retroviral transduction of c-Maf was able to induce IL-10 expression in Stat6 deficient CD4 and CD8 T cells, and c-Maf directly transactivated IL-10 gene expression through binding to a MARE motif in the IL-10 promoter. Together, these data reveal a novel role for c-Maf in regulating T effector development, and suggest that TGFbeta may antagonize Th17 immunity by IL-10 production through c-Maf induction.
2009-03-03 | GSE15029 | GEO
Project description:IL-10 production by Th17 cells is critical for limiting autoimmunity and inflammatory responses. Gene array analysis on Stat6 and T-bet double deficient Th17 cells identified the Th2 transcription factor c-Maf to be synergistically up-regulated by IL-6 plus TGFbeta, and associated with Th17 IL-10 production. Both c-Maf and IL-10 induction during Th17 polarization depended on Stat3, but not Stat6 or Stat1, and mechanistically differed from IL-10 regulation by Th2 or IL-27 signals. TGFbeta was also synergistic with IL-27 to induce c-Maf, and induced Stat1 independent IL-10 expression in contrast to IL-27 alone. Retroviral transduction of c-Maf was able to induce IL-10 expression in Stat6 deficient CD4 and CD8 T cells, and c-Maf directly transactivated IL-10 gene expression through binding to a MARE motif in the IL-10 promoter. Together, these data reveal a novel role for c-Maf in regulating T effector development, and suggest that TGFbeta may antagonize Th17 immunity by IL-10 production through c-Maf induction. Our recent studies showed that IL-6 combined with TGFbeta differed from IL-6 combined with IL-23 for IL-10 production and pathogenic activities in CD4 T cells deficient in Stat6 and T-bet, despite similar IL-17 production. We performed gene array analysis on Stat6 and T-bet double deficient cells. We rationalized that by comparing gene expression in cells treated with IL-6 plus TGFbeta versus TGFbeta alone, we would be able to identify genes specific for standard Th17 polarization, and responsible for both IL-17 and IL-10 expression. By next comparing gene expression in cells treated with IL-6 plus TGFbeta versus IL-6 plus IL-23, we could eliminate molecules involved solely in IL-17 regulation, and obtain genes specifically responsible for IL-10 regulation.
2009-03-03 | E-GEOD-15029 | biostudies-arrayexpress
Project description:Development of persistent Th2 responses in asthma and chronic helminth infections are a major health concern. IL-10 has been identified as a critical regulator of Th2 immunity, but mechanisms for controlling Th2 effector function remain unclear. IL-10 also has paradoxical effects on Th2-associated pathology, with IL-10 deficiency resulting in increased Th2-driven inflammation but also reduced airway hyperreactivity (AHR), mucus hypersecretion, and fibrosis. We demonstrate that increased IL-13 receptor alpha 2 (IL-13Ralpha2) expression is responsible for the reduced AHR, mucus production, and fibrosis in BALB/c IL-10(-/-) mice. Using models of allergic asthma and chronic helminth infection, we demonstrate that IL-10 and IL-13Ralpha2 coordinately suppress Th2-mediated inflammation and pathology, respectively. Although IL-10 was identified as the dominant antiinflammatory mediator, studies with double IL-10/IL-13Ralpha2-deficient mice illustrate an indispensable role for IL-13Ralpha2 in the suppression of AHR, mucus production, and fibrosis. Thus, IL-10 and IL-13Ralpha2 are both required to control chronic Th2-driven pathological responses.
| S-EPMC1978425 | biostudies-literature
Project description:We previously showed that adeno-associated virus 2 (AAV2) mediated subretinal delivery of human interferon-alpha (IFN-α) could effectively inhibit experimental autoimmune uveoretinitis (EAU). In this study we investigated whether subretinal injection of both AVV2.IFN-α and AAV2.IL-4 had a stronger inhibition on EAU activity. B10RIII mice were subretinally injected with AAV2.IFN-α alone (1.5×10(7) vg), AAV2.IL-4 alone (3.55×10(7) vg), and AAV2.IFN-α combined with AAV2.IL-4. PBS, AAV2 vector encoding green fluorescent protein (AAV2.GFP) (5×10(7) vg) was subretinally injected as a control. IFN-α and IL-4 were effectively expressed in the eyes from three weeks to three months following subretinal injection of AAV2 vectors either alone or following combined administration and significantly attenuated EAU activity clinically and histopathologically. AAV2.IL-4 showed a better therapeutic effect as compared to AAV2.IFN-α. The combination of AAV2.IL-4 and AAV2.IFN-α was not significantly different as compared to AAV2.IL-4 alone. There was no difference concerning DTH (delayed-type hypersensitivity) reaction, lymphocyte proliferation and IL-17 production among the investigated treatment groups, suggesting that local retinal gene delivery did not affect the systemic immune response.
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Project description:While others have described gene expression patterns in humans with inflammatory bowel diseases and animals with chemically induced colitis, a genome-wide comparison of gene expression in genetically susceptible animals that develop spontaneous colitis has not been reported.We used microarray technology to compare gene expression profiles in cecal specimens from specific pathogen-free IL10-deficient (IL10-/-) mice with colitis and normal wildtype (WT) mice. RNA isolated from ceca of IL10-/- and WT mice was subjected to microarray analysis. The results were confirmed by real-time polymerase chain reaction (PCR) and immunofluorescence microscopy of selected molecules. Expression of the selected genes in dextran sodium sulfate (DSS)-treated mice with colitis and epithelial cell lines activated with pathophysiologic stimuli was measured by real-time PCR.Histological inflammation of the colon and IL-12/23p40 secretion from intestinal explants were greater in IL10-/- and DSS-treated mice versus WT and untreated mice. Microarray analysis demonstrated >10-fold induction of the following molecules in the ceca of IL10-/- mice: mitochondrial ribosomal protein-L33, aquaporin-4, indoleamine-pyrrole-2,3-dioxygenase, and MHC class II with 63, 25, 20, and 12-fold increases, respectively. Cytochrome-P450, pancreatic lipase-related protein-2, and transthyretin were downregulated in IL10-/- mice. MHC II was increased throughout the colon, and aquaporin-4 was increased in the basolateral aspect of cecal epithelial cells. MHC II mRNA was increased in epithelial cells treated with IFN-gamma, but not TNF or Toll-like receptor ligands.Although most upregulated genes in experimental colitis are immune-related, aquaporin-4 and mitochondrial ribosomal protein-L33, which have not been previously associated with inflammation, were most highly upregulated.
| S-EPMC2763592 | biostudies-literature
Project description:Endotoxin (LPS), a Gram-negative cell wall component, has potent proinflammatory properties. Acute LPS exposure causes airway inflammation; chronic exposure causes airway hyperreactivity and remodeling. IL-10 is an important antiinflammatory cytokine, which is decreased in patients with airway disease, such as asthma and cystic fibrosis. To examine the physiologic and therapeutic role of IL-10 in acute and chronic LPS-induced airway disease. Mice were exposed to aerosolized LPS once or daily for 4 wk. Endpoints were airway inflammation, airway reactivity to methacholine, extracellular matrix protein expression, and histologic analysis. IL-10-deficient mice developed significantly enhanced airway cellularity and remodeling when compared with C57BL/6 mice after chronic LPS inhalation. However they demonstrated less airway hyperreactivity associated with higher inducible nitric oxide synthase (iNOS), endothelial NOS (eNOS), and lung lavage fluid nitrite levels. In a bone marrow transplantation model, the IL-10 antiinflammatory effect was dependent on the hematopoietic but not on the parenchymal IL-10 expression. Induced epithelial human IL-10 expression protected from the LPS effects and led to decreased collagen production. IL-10 attenuates chronic LPS-induced airway inflammation and remodeling. Physiologically, the antiinflammatory effect of IL-10 is mediated by hematopoietic cells. Therapeutically, adenovirus-driven expression of human IL-10 in airway epithelia is sufficient for its protective effect on inflammation and remodeling. The role of IL-10 on airway hyperreactivity is complex: IL-10 deficiency protects against LPS-induced hyperreactivity, and is associated with higher eNOS, iNOS, and airway nitrate levels.
| S-EPMC2643294 | biostudies-other
Project description:Background & aimsProgressive fibrosis contributes to the morbidity of several chronic diseases; it typically develops slowly, so the mechanisms that control its progression and resolution have been difficult to model. The proteins interleukin (IL)-10, IL-12p40, and IL-13Rα2 regulate hepatic fibrosis following infection with the helminth parasite Schistosoma mansoni. We examined whether these mediators interact to slow the progression of hepatic fibrosis in mice with schistosomiasis.MethodsIL-10(-/-), IL-12/23(p40)(-/-), and IL-13Rα2(-/-) mice were crossed to generate triple knockout (TKO) mice. We studied these mice to determine whether the simultaneous deletion of these 3 negative regulators of the immune response accelerated mortality from liver fibrosis following infection with S mansoni.ResultsInduction of inflammation by S mansoni, liver fibrosis, and mortality increased greatly in TKO mice compared with wild-type mice; 100% of the TKO mice died by 10 weeks after infection. Morbidity and mortality were associated with the development of portal hypertension, hepatosplenomegaly, gastrointestinal bleeding, ascites, thrombocytopenia, esophageal and gastric varices, anemia, and increased levels of liver enzymes, all features of advanced liver disease. IL-10, IL-12p40, and IL-13Rα2 reduced the production and activity of the profibrotic cytokine IL-13. A neutralizing antibody against IL-13 reduced the morbidity and mortality of the TKO mice following S mansoni infection.ConclusionsIL-10, IL-12p40, and IL-13Rα2 act cooperatively to suppress liver fibrosis in mice following infection with S mansoni. This model rapidly reproduces many of the complications observed in patients with advanced cirrhosis, so it might be used to evaluate the efficacy of antifibrotic reagents being developed for schistosomiasis or other fibrotic diseases associated with a T-helper 2 cell-mediated immune response.
| S-EPMC3221932 | biostudies-literature