Reduced responsiveness of HLA-B27 transgenic rat cells to TGF-β and IL-10-mediated regulation of IFN-γ production

Abstract

Background: We have reported that commensal luminal bacterial components induce an active in vitro IFN-γ response in mesenteric lymph node (MLN) and intestinal cells from specific pathogen-free (SPF) HLA-B27 transgenic (TG) rats with chronic colitis but not in cells from non-diseased SPF non-TG, germ-free (GF) non-TG or GF TG rats. Methods: The study examined IL-12 stimulation of MLN IFN-γ responses to luminal bacteria and regulation of these responses by suppressive cytokines. Results: Exogenous IL-12 significantly increased the bacterial lysate-induced IFN-γ response in SPF TG MLN cells, while bacterial lysate and IL-12 synergistically induced IFN-γ from low baseline levels in cells obtained from both SPF and GF non-TG rats, and in GF TG cells. TGF-β fully counteracted the effects of IL-12 and bacterial lysate on non-TG cells by almost completely inhibiting IFN-γ production. In contrast, TG cells were less responsive to TGF-β-mediated downregulation with a substantial residual IFN-γ response to IL-12 plus bacterial lysate. Further experiments showed that CD4+/CD25+ cells had no inhibitory effect on the IFN-γ production and were not required for TGF-β-mediated suppression. Addition of exogenous IL-10 also partially inhibited IFN-γ production by non-TG cells but did not affect TG cells. Conversely, exogenous IL-12 preferentially suppressed bacterial lysate-induced TGF-β and IL-10 production in TG rat cells. Conclusions: An attenuated response to regulatory signals leads to uncontrolled potentiated induction of effector IFN-γ responses to commensal bacteria in HLA-B27 TG rats that spontaneously develop chronic intestinal inflammation. Copyright © 2008 Crohn's & Colitis Foundation of America, Inc.