Cytokines Mediating the Induction of Chronic Colitis and Colitis-Associated Fibrosis

To investigate the immunopathogenesis of inflammation-associated fibrosis we analyzed the chronic colitis and late-developing fibrosis occurring in BALB/c mice administered weekly doses of intra-rectal trinitrobenzene sulfonic acid (TNBS). We showed first in this model that an initial Th1 response involving IL-12p70 and IFN-γ subsides after three weeks to be supplanted by an IL-23/IL-25 response beginning after 4–5 weeks. This evolution is followed by gradually increasing production of IL-17 and cytokines ordinarily seen in a Th2 response, particularly IL-13, which reaches a plateau at 8–9 weeks. We then show that IL-13 production results in the induction of an IL-13 receptor formerly thought to function only as a decoy receptor, IL-13Rα(2), and this receptor is critical to the production of TGF-β(1) and the onset of fibrosis. Thus, if IL-13 signaling through this receptor is blocked by administration of soluble IL-13Rα(2)-Fc, or by administration of IL-13Rα(2)–specific siRNA, TGF-β(1) is not produced and fibrosis does not occur. These studies show that in chronic TNBS colitis, fibrosis is dependent on the development of an IL-13 response that acts through a novel cell-surface-expressed IL-13 receptor to induce TGF-β(1).