Induction of IL-13 Triggers TGF-β1-Dependent Tissue Fibrosis in Chronic 2,4,6-Trinitrobenzene Sulfonic Acid Colitis

Abstract

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 intrarectal 2,4,6-trinitrobenzene sulfonic acid. We showed first in this model that an initial Th1 response involving IL-12p70 and IFN-γ subsides after 3 wk to be supplanted by an IL-23/IL-25 response beginning after 4–5 wk. 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 wk. In vitro stimulation studies suggest that this IL-13 production is dependent on IL-23 and IL-25, but not on IL-12p70. We then show that IL-13 production results in the induction of an IL-13R formerly thought to function only as a decoy receptor, IL-13Rα2, and this receptor is critical to the production of TGF-β1 and the onset of fibrosis. Thus, if IL-13 signaling through this receptor is blocked by administration of soluble IL-13Rα2-Fc, or by administration of IL-13Rα2-specific small interfering RNA, TGF-β1 is not produced and fibrosis does not occur. These studies show that in chronic 2,4,6-trinitrobenzene sulfonic acid colitis, fibrosis is dependent on the development of an IL-13 response that acts through a novel cell surface-expressed IL-13R to induce TGF-β1. A similar mechanism may obtain in certain forms of human inflammatory bowel disease.

Inhibitory Effect of Recombinant IL-25 on the Development of Dextran Sulfate Sodium-Induced Experimental Colitis in Mice

“…Our results are in line with that of TNBS-induced colitis whereby both IL-25 and IL-23 were shown to appear together (21). In this most recent study, IL-25 was reported to facilitate the production of TGF-1 through induction of IL-13 (21).…”

“…Our results are in line with that of TNBS-induced colitis whereby both IL-25 and IL-23 were shown to appear together (21). In this most recent study, IL-25 was reported to facilitate the production of TGF-1 through induction of IL-13 (21). TGF-1 has long been recognized to exert an anti-inflammatory effect and under certain conditions potentates inflammation (22).…”

Distinct roles for IL-13 and IL-4 via IL-13 receptor α1 and the type II IL-4 receptor in asthma pathogenesis

“…In contrast, IL-13 is hypothesized to execute its IL-4R␣-dependent effects solely through the type II IL-4R but may use a signaling complex that does not require IL-4R␣ (3). In addition, IL-13R␣2, an IL-13 decoy receptor (4), has been recently reported to also mediate IL-13 signaling and induce TGF-␤ production (5,6). Thus, the assumption that IL-13R␣1 is the main signaling receptor for IL-13 needs definitive proof.…”

Neutrophil Elastase Inhibitor Suppresses Il-17 Based Inflammation of Murine Experimental Colitis

“…Accumulating evidence also suggests that Th17 cells have a pathogenic role in experimental models of IBD. For example, up -regulation of IL -17 occurs in mice with acute and relapsing TNBS colitis, and blockade of IL -17R signals protects animals against the development of acute TNBS colitis 32,33) . We have also shown that administration of NE inhibitor suppresses expression of IL -17 in the colon.…”