Zusammenfassung
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 ...
Zusammenfassung
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.
Altmetric