These results demonstrate that IL-17R signaling plays a critical role in the development of TNBS-induced colitis and may represent a target for therapeutic intervention for IBD.

Chronic ethanol (EtOH) abuse results in the development of steatosis, alcoholic hepatitis, and cirrhosis. Augmented TNF-α production by macrophages and Kupffer cells and signaling via the p55 TNF receptor have been shown to be critical for these effects of chronic EtOH; however, the molecular mechanisms leading to augmented TNF-α production remain unclear. Using cell culture models and in vivo studies we demonstrate that chronic EtOH results in increased TNF-α transcription, which is independent of NF-κB. Using reporter assays and chromatin immunoprecipitation we found that this increased transcription is due to increased IRF-3 binding to and transactivation of the TNF promoter. As IRF-3 is downstream from the TLR4 adaptor TIR-domain-containing adapter-inducing IFN-β (Trif), we demonstrate that macrophages from Trif−/− mice are resistant to this dysregulation of TNF-α transcription by EtOH in vitro as well as EtOH-induced steatosis and TNF dysregulation in vivo. These data demonstrate that the Trif/IRF-3 pathway is a target to ameliorate liver dysfunction associated with chronic EtOH.

Inflammatory bowel diseases (IBD) are characterized by recurrent inflammation in the gastrointestinal tract. Infiltration of CD4+ lymphocytes and neutrophils is one of the predominant features in IBD. Recently, interleukin (IL)-23 and the downstream T-cell derived cytokine IL-17 have been found to be elevated in IBD patients. However, the role of IL-17 and IL-17 receptor (IL-17R) signaling in gastrointestinal inflammation is unknown. To examine their role, we investigated colonic inflammation in wild-type or IL-17R KO mice. Using a model of TNBS-induced colitis, we found that IL-17 was produced in colon tissue at 24 and 48 hours. IL-17R KO mice were significantly protected against TNBS-induced weight loss, IL-6 production, local MIP-2 induction, as well as colonic inflammation. This protection occurred in the presence of equivalent induction of local IL-23 and higher levels of IL-12p70 and IFN-gamma in IL-17R KO mice compared to wild-type mice. Moreover, IL-17R KO mice exhibited a reduced tissue neutrophil infiltration as assessed by myeloperoxidase activity. Furthermore, overexpression of an IL-17R IgG1 fusion protein significantly attenuated colonic inflammation after TNBS challenge. These results demonstrate that IL-17 and IL-17R signaling play a critical role in the development of TNBS-induced colitis and may represent a target for therapeutic intervention for IBD.

Conclusion:We have for the first time directly measured the force generated by HSCs after a range of days in culture. Both the force of contraction and the number of cells within a cross-section of a gel increased with the number of days in culture. This suggests that the time-dependent increase in force generation may be due to an increase in HSC number rather than an increase in force generated by each cell.

Inflammatory bowel diseases (IBD) are characterized by recurrent inflammation in the gastrointestinal tract. Infiltration of CD4+ lymphocytes and neutrophils is one of the predominant features in IBD. Recently, interleukin (IL)-23 and the downstream T-cell derived cytokine IL-17 have been found to be elevated in IBD patients. However, the role of IL-17 and IL-17 receptor (IL-17R) signaling in gastrointestinal inflammation is unknown. To examine their role, we investigated colonic inflammation in wild-type or IL-17R KO mice. Using a model of TNBS-induced colitis, we found that IL-17 was produced in colon tissue at 24 and 48 hours. IL-17R KO mice were significantly protected against TNBS-induced weight loss, IL-6 production, local MIP-2 induction, as well as colonic inflammation. This protection occurred in the presence of equivalent induction of local IL-23 and higher levels of IL-12p70 and IFN-gamma in IL-17R KO mice compared to wild-type mice. Moreover, IL-17R KO mice exhibited a reduced tissue neutrophil infiltration as assessed by myeloperoxidase activity. Furthermore, overexpression of an IL-17R IgG1 fusion protein significantly attenuated colonic inflammation after TNBS challenge. These results demonstrate that IL-17 and IL-17R signaling play a critical role in the development of TNBS-induced colitis and may represent a target for therapeutic intervention for IBD.