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1-Dependent Tissue Fibrosis in Chronic 2,4,6-Trinitrobenzene Sulfonic Acid Colitis
* Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and
Department of Surgery, University of Regensburg, Regensburg, Germany
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-
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-13R
2, and this receptor is critical to the production of TGF-
1 and the onset of fibrosis. Thus, if IL-13 signaling through this receptor is blocked by administration of soluble IL-13R2-Fc, or by administration of IL-13R2-specific small interfering RNA, TGF-1 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-1. A similar mechanism may obtain in certain forms of human inflammatory bowel disease.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 Address correspondence and reprint requests to Dr. Stefan Fichtner-Feigl, Department of Surgery, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany. E-mail address: stefan.fichtner{at}klinik.uni-regensburg.de
2 Abbreviations used in this paper: CD, Crohn’s disease; TNBS, 2,4,6-trinitrobenzene sulfonic acid; siRNA, small interfering RNA; HVJ-E, HVJ envelope; LPMC, lamina propria mononuclear cell; pSmad3, phosphorylated Smad3.
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