| First Author | Fichtner-Feigl S | Year | 2008 |
| Journal | Gastroenterology | Volume | 135 |
| Issue | 6 | Pages | 2003-13, 2013.e1-7 |
| PubMed ID | 18938165 | Mgi Jnum | J:145622 |
| Mgi Id | MGI:3835689 | Doi | 10.1053/j.gastro.2008.08.055 |
| Citation | Fichtner-Feigl S, et al. (2008) IL-13 signaling via IL-13R alpha2 induces major downstream fibrogenic factors mediating fibrosis in chronic TNBS colitis. Gastroenterology 135(6):2003-13, 2013.e1-7 |
| abstractText | 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)-beta1. In the present study, we sought to determine the fibrogenic downstream events set in motion by such signaling. METHODS: 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-beta1 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-beta1 signaling results in severe inhibition of expression of colonic insulin-like growth factor (IGF)-I and early growth response gene (Egr)-1, factors known to initiate and sustain fibrosis. We then showed that Egr-1 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-beta1 activation. Finally, we showed that IGF-I (together with TGF-beta1) 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-beta1 activation, IGF-I and Egr-1 expression, myofibroblast apoptosis, and myofibroblast production of collagen. |
