Deletion of SOCS2 Reduces Post-Colitis Fibrosis via Alteration of the TGFβ Pathway

Abstract

Inflammatory bowel disease (IBD) is an immunologically mediated chronic intestinal disorder. Growth hormone (GH) administration enhances mucosal repair and decreases intestinal fibrosis in patients with IBD. In the present study, we investigated the effect of cellular sensitivity to GH via suppressor of cytokine signaling 2 (SOCS2) deletion on colitis and recovery. To induce colitis, wild type and SOCS2 knockout (SOCS2−/−) mice were treated with 3% dextran sodium sulphate (DSS), followed by a recovery period. SOCS2−/− mice showed higher disease activity during colitis with increased mRNA expression of the pro-inflammatory cytokines nitric oxide synthase 2 (NOS2) and interleukin 1 β (IL1-β). At recovery time point, SOCS2−/− showed better recovery with less fibrosis measured by levels of α-SMA and collagen deposition. Protein and mRNA expressions of transforming growth factor beta β1 (TGF-β1) receptors were significantly lower in SOCS2−/− mice compared to wild-type littermates. Using an in vivo bromodeoxyuridine (BrdU) proliferation assay, SOCS2−/− mice showed higher intestinal epithelial proliferation compared to wild-type mice. Our results demonstrated that deletion of the SOCS2 protein results in higher growth hormone sensitivity associated with higher pro-inflammatory signaling; however, it resulted in less tissue damage with less fibrotic lesions and higher epithelial proliferation, which are markers of GH-protective effects in IBD. This suggests a pleiotropic effect of SOCS2 and multiple cellular targets. Further study is required to study role of SOCS2 in regulation of TGFβ-mothers against the decapentaplegic homolog (Smad) pathway.

A whole-genome reference panel of 14,393 individuals for East Asian populations accelerates discovery of rare functional variants

“…The expression of SOCS2 can be induced by various cytokines including growth hormone and insulin-like growth factor ( 40 ). SOCS2 protein is involved in insulin-like growth factor 1 (IGF-1) receptor signaling and in the TGF-β pathway ( 41 ). Socs2 −/− mice show increased long bone length and body weight, and most organs are enlarged ( 42 ).…”

Intestinal Fibrosis in Inflammatory Bowel Disease and the Prospects of Mesenchymal Stem Cell Therapy

“…Stricture is a serious problem with an 8% incidence in UC, whereas fibrostenotic complications lead to stricture formation (narrowing), intestinal obstruction, and a need for surgical intervention, and as such, is one of the largest unresolved clinical challenges in IBD (11). The development of intestinal fibrosis is complex and the specific mechanism has not been understood until today, however, researchers widely believe that the progression of intestinal fibrosis includes the following steps: cells injury, production of transforming growth factor (TGF-b1), recruitment of inflammatory cells, and activation of myofibroblasts and collagen-producing cells (12)(13)(14)(15)(16).…”