Interleukin11 Reduces TLR4Induced Colitis in TLR2Deficient Mice and Restores Intestinal STAT3 Signaling (original) (raw)
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Cellular Microbiology, 2007
Inflammatory bowel diseases and infectious gastroenteritis likely occur when the integrity of intestinal barriers is disrupted allowing luminal bacterial products to cross into the intestinal mucosa, stimulating immune cells and triggering inflammation. While specific Toll-like receptors (TLR) are involved in the generation of inflammatory responses against enteric bacteria, their contributions to the maintenance of intestinal mucosal integrity are less clear. These studies investigated the role of TLR2 in a model of murine colitis induced by the bacterial pathogen Citrobacter rodentium. C. rodentium supernatants specifically activated TLR2 in vitro while infected TLR2-/mice suffered a lethal colitis coincident with colonic mucosal ulcerations, bleeding and increased cell death but not increased pathogen burden. TLR2-/mice suffered impaired epithelial barrier function mediated via zonula occludens (ZO)-1 in naïve mice and claudin-3 in infected mice, suggesting this could underlie their susceptibility. TLR2 deficiency was also associated with impaired production of IL-6 by bone marrow-derived macrophages and infected colons cultured ex vivo. As IL-6 has antiapoptotic and epithelial repair capabilities, its reduced expression could contribute to the impaired mucosal integrity. These studies report for the first time that TLR2 plays a critical role in maintaining intestinal mucosal integrity during infection by a bacterial pathogen.
American Journal of Physiology-Gastrointestinal and Liver Physiology, 2004
The interleukin-2-deficient (IL-2−/−) mouse model of ulcerative colitis was used to test the hypothesis that colonic epithelial cells (CEC) directly respond to bacterial antigens and that alterations in Toll-like receptor (TLR)-mediated signaling may occur during the development of colitis. TLR expression and activation of TLR-mediated signaling pathways in primary CEC of healthy animals was compared with CEC in IL-2−/−mice during the development of colitis. In healthy animals, CEC expressed functional TLR, and in response to the TLR4 ligand LPS, proliferated and secreted the cytokines IL-6 and monocyte chemoattractant protein-1 (MCP-1). However, the TLR-responsiveness of CEC in IL-2−/−mice was different with decreased TLR4 responsiveness and augmented TLR2 responses that result in IL-6 and MCP-1 secretion. TLR signaling in CEC did not involve NF-κB (p65) activation with the inhibitory p50 form of NF-κB predominating in CEC in both the healthy and inflamed colon. Development of coli...
Gut
Background The extent to which numerous strains of genetically engineered mice, including mice lacking Toll-like receptor 5 (T5KO), display colitis is environment dependent. Gut microbiota underlie much of the variation in phenotype. Accordingly, embryonic rederivation of T5KO mice ameliorated their spontaneous colitis despite only partially correcting elevated proinflammatory gene expression. It was postulated that endogenous antiinflammatory pathways mediated the absence of overt inflammation in these mice when their gut microbiota were reset. Consequently, it was hypothesised that neutralisation of the anti-inflammatory cytokine interleukin 10 (IL-10) might induce uniform colitis in T5KO mice, and thus provide a practical means to study mechanisms underlying their inflammation. Methods Two distinct strains of non-colitic T5KO mice, as well as mice lacking MyD88, Toll-like receptor 4 (TLR4), IL-1 receptor (IL-1R) and various double knockouts (DKOs) were treated weekly for 4 weeks with 1 mg/mouse of IL-10 receptor neutralising antibody (IL-10R mAb) and colitis assayed 1 week later. The composition of the caecal microbiota was determined by 454 pyrosequencing of 16S rRNA genes. Results Anti-IL-10R mAb treatment led to severe uniform intestinal inflammation in both strains of T5KO mice. Such neutralisation of IL-10 signalling did not cause colitis in wild-type littermates nor mice lacking TLR4, MyD88 or IL-1R. The susceptibility of T5KO mice to this colitis model was not rescued by absence of TLR4 in that T4/T5 DKO mice displayed severe colitis in response to anti-IL-10R mAb treatment. IL-1b signalling was crucial for this colitis model in that IL-1R/T5 DKOs were completely protected from colitis in response to IL-10R mAb treatment. Lastly, it was observed that blockade of IL-10R function was associated with changes in the composition of gut microbiota, which were observed in mice that were susceptible and resistant to IL-10R mAb-induced colitis. Conclusion Regardless of whether they harbour a colitogenic microbiota, loss of TLR5 predisposes mice to colitis triggered by immune dysregulation via an IL-1b-dependent pathway.
Clinical & …, 2008
Inflammatory bowel disease (IBD) may result from exaggerated stimulation of the mucosal immune system by luminal bacterial flora. Bacterial products are recognized by pattern recognition receptors such as Toll-like receptors (TLRs), which are key regulators of the innate immune system. Therefore, the expression of TLR2, TLR3 and TLR4 in colonic biopsy samples taken from children with active IBD were studied and compared to controls. Colonic biopsy samples were collected from macroscopically inflamed and noninflamed regions of the mucosa of 12 children with freshly diagnosed IBD (fdIBD) and 23 children with relapsed IBD (rIBD). Specimens were also obtained from eight controls. TLR2, TLR3 and TLR4 mRNA expression and protein levels were determined by real-time reverse transcription polymerase chain reaction (RT-PCR) and Western blot. We found higher TLR2 and TLR4 mRNA and protein levels in the inflamed colonic mucosa of children with fdIBD and rIBD compared to controls. In the non-inflamed colonic mucosa of children with fdIBD and rIBD, TLR2 and TLR4 mRNA and protein levels were similar to controls. TLR2 and TLR4 mRNA and protein levels also did not differ between children with fdIBD or rIBD in either inflamed or noninflamed colonic mucosa. TLR3 mRNA expression and protein levels were similar in all groups studied. Our results of increased levels of TLR2 and TLR4 in the inflamed colonic mucosa of children with IBD confirm the hypothesis that innate immunity has an important role in the pathogenesis of this disease.
Clinical and Experimental Immunology, 2007
Inflammatory bowel disease (IBD) may result from exaggerated stimulation of the mucosal immune system by luminal bacterial flora. Bacterial products are recognized by pattern recognition receptors such as Toll-like receptors (TLRs), which are key regulators of the innate immune system. Therefore, the expression of TLR2, TLR3 and TLR4 in colonic biopsy samples taken from children with active IBD were studied and compared to controls. Colonic biopsy samples were collected from macroscopically inflamed and non-inflamed regions of the mucosa of 12 children with freshly diagnosed IBD (fdIBD) and 23 children with relapsed IBD (rIBD). Specimens were also obtained from eight controls. TLR2, TLR3 and TLR4 mRNA expression and protein levels were determined by real-time reverse transcription polymerase chain reaction (RT–PCR) and Western blot. We found higher TLR2 and TLR4 mRNA and protein levels in the inflamed colonic mucosa of children with fdIBD and rIBD compared to controls. In the non-inflamed colonic mucosa of children with fdIBD and rIBD, TLR2 and TLR4 mRNA and protein levels were similar to controls. TLR2 and TLR4 mRNA and protein levels also did not differ between children with fdIBD or rIBD in either inflamed or non-inflamed colonic mucosa. TLR3 mRNA expression and protein levels were similar in all groups studied. Our results of increased levels of TLR2 and TLR4 in the inflamed colonic mucosa of children with IBD confirm the hypothesis that innate immunity has an important role in the pathogenesis of this disease.
Corticotropin-Releasing Factor Regulates TLR4 Expression in the Colon and Protects Mice From Colitis
Gastroenterology, 2010
BACKGROUND & AIMS: Defects in the colonic innate immune response have been associated with inflammatory bowel disease (IBD). Corticotropin-releasing hormone (CRH, or corticotropin-releasing factor [CRF]) is a neuropeptide that mediates the stress response in humans, is an immunomodulatory factor with proinflammatory effects, and regulates transcription of Toll-like receptors (TLR)-2 and TLR4. We investigated the role of CRF in an innate immunity-dependent mouse model of IBD. METHODS: Crh Ϫ/Ϫ and wild-type (Crh ϩ/ϩ) mice, which are glucocorticoid insufficient, were given dextran sodium sulfate in their drinking water to induce colitis; in some experiments, mice were also given glucocorticoids. Phenotypes of mice were compared; tissues were analyzed by histology and for expression of immune mediators. RESULTS: Crh Ϫ/Ϫ mice had more colonic inflammation than Crh ϩ/ϩ mice, characterized by reduced numbers of crypts and severe epithelial damage and ulcerations. Colonic tissue levels of the proinflammatory factors interleukin-12 and prostaglandin E 2 were increased in the Crh Ϫ/Ϫ mice. Colons of Crh Ϫ/Ϫ mice expressed lower levels of Tlr4 than wild-type mice before, but not after, colitis was induced. Administration of glucocorticoid at low levels did not prevent Crh Ϫ/Ϫ mice from developing severe colitis. Crh Ϫ/Ϫ mice were unable to recover from acute colitis, as indicated by their increased death rate. CONCLUSIONS: Mice deficient in CRF down-regulate TLR4 and are more susceptible to dextran sodium sulfate-induced colitis. CRF has antiinflammatory effects in innate immunity-dependent colitis and its recovery phase; these are independent of glucocorticoid administration. CRF might therefore be developed as a therapeutic target for patients with IBD.