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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.
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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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