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

Amna Al-Araimi,Shadia Al Sinawi,Asma Bani Oraba,Amira Al Kharusi,Matar M Al-Maney,Fahad Zadjali,Ibrahim Al-Haddabi

doi:10.3390/ijms21093073

Amna Al-Araimi, Shadia Al Sinawi + Show 5 more

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https://doi.org/10.3390/ijms21093073

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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.

Highlights

Inflammatory bowel disease (IBD) describes two conditions: Crohn’s disease and ulcerative colitis, in which chronic inflammation is a hallmark
suppressor of cytokine signaling 2 (SOCS2)−/− mice showed increased growth hormone (GH) sensitivity during the active colitis and recovery periods, and this is associated with increased intestinal epithelial turnover and less collagen deposition at the recovery phase
Disease activity during induction of colitis and recovery was higher in SOCS2−/− mice, which was evident during the macroscopic (Figure 1C) and microscopic (Figure 1D) evaluation of disease activity and increased expression of proinflammatory cytokines at the recovery phase (Figure 2A)

Summary

Introduction

Inflammatory bowel disease (IBD) describes two conditions: Crohn’s disease and ulcerative colitis, in which chronic inflammation is a hallmark. This results from an inappropriate immune response with a sustained hyperactivity and proliferation of immune cells. An imbalance in cellular signaling, mediated by hormones and inflammatory cytokines, leads to disruptive intestinal homeostasis, mucosal damage and defective repair [1,2]. In a small number of Crohn’s disease patients, administration of growth hormone (GH) showed positive results, with an improved colitis activity index and less need for immunosuppressors [2,3]. An alternative to the administration of GH is to increase the cellular sensitivity toward GH, which could be more beneficial to avoid exogenous doses of GH and, avoiding the reported side effects [12]

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