Fichtner-Feigl, Stefan and Young, Cheryl A. and Kitani, Atsushi and Geissler, Edward K. and Schlitt, Hans-Juergen and Strober, Warren (2008) IL-13 Signaling via IL-13R alpha(2) Induces Major Downstream Fibrogenic Factors Mediating Fibrosis in Chronic TNBS Colitis. GASTROENTEROLOGY, 135 (6). pp. 2003-2013. ISSN 0016-5085,
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Background & Aims: Previous studies have shown that fibrosis developing in chronic experimental colitis is driven by interleukin (IL)-13 signaling via IL-13R alpha(2) and the production of transforming growth factor (TGF)-beta 1. In the present study, we sought to determine the fibrogenic downstream events set in motion by such signaling. Metho : Experimental colitis with late-onset intestinal fibrosis was induced by weekly intrarectal administration of trinitrobenzene sulfonic acid (TNBS) to BALB/c mice. Blockade of IL-13 signaling via IL-13R alpha(2) and TGF-beta 1 signaling was achieved by the administration of small interfering RNA or decoy oligonucleotides that target promoter sequences of signaling components of these receptors. Effects of blockade were determined by enzyme-linked immunosorbent assay or Western blotting detecting specific key fibrogenic factors and by measurement of collagen production. Results: Initially, we showed that abrogation of IL-13 activity via blockade of IL-13R alpha(2) and TGF-beta 1 signaling results in severe inhibition of expression of colonic insulin-like growth factor (IGF)-I and early growth response gene (Egr)-I, factors known to initiate and sustain fibrosis. We then showed that Egr-I was necessary early in the fibrotic process for caspase-mediated apoptosis of myofibroblasts and the production of urokinase plasminogen activator, a protein that enhances TGF-beta 1 activation. Finally, we showed that IGF-I (together with TGF-beta 1) acts later in the process to stimulate myofibroblasts to deposit collagen in the colon. Conclusions: These studies establish that IL-13 signaling via the IL-13R alpha(2) is a key initiation point for a complex fibrotic program in the colon consisting of TGF-beta 1 activation, IGF-I and Egr-1 expression, myofibroblast apoptosis, and myofibroblast production of collagen.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | INFLAMMATORY-BOWEL-DISEASE; HVJ-ENVELOPE VECTOR; NF-KAPPA-B; IGF-I; CROHNS-DISEASE; TISSUE FIBROSIS; MURINE MODEL; APOPTOSIS; CELLS; TGF-BETA-1; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Chirurgie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 14 Oct 2020 10:09 |
| Last Modified: | 14 Oct 2020 10:09 |
| URI: | https://pred.uni-regensburg.de/id/eprint/29957 |
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