Critical role of ROCK2 activity in facilitating mucosal CD4 + T cell activation in inflammatory bowel disease

J Autoimmun. 2018 May;89:125-138. doi: 10.1016/j.jaut.2017.12.009. Epub 2017 Dec 19.

Abstract

Rho-associated kinase (ROCK) has been found to be involved in the pathogenesis of a variety of autoimmune diseases, but the role of ROCK in inflammatory bowel disease (IBD) is still elusive. In this study, we demonstrated that the levels of ROCK2, but not ROCK1, activity were significantly upregulated in peripheral blood mononuclear cells (PBMC) and inflamed mucosa from IBD patients using a ROCK activity assay, and that ROCK2 activity in intestinal mucosa was positively correlated with disease severity. Stimulation with TNF markedly upregulated ROCK2 activity in IBD CD4+ T cells through NF-κB signaling. Blockade of ROCK2 activity using Slx-2119 significantly suppressed proinflammatory cytokines in inflamed mucosa from IBD patients including IFX-unresponsive CD patients, and inhibited IBD CD4+ T cells to differentiate into Th1 and Th17 cells through downregulating phosphorylated Stat1 and Stat3, but promoted Treg cell differentiation through upregulating phosphorylated Stat5. Furthermore, oral administration of Slx-2119 markedly ameliorated intestinal mucosal inflammation in TNBS-induced colitis in mice and decreased proinflammatory cytokines productions in inflamed colon. Our data indicate that ROCK2 plays a critical role in inducing mucosal T cell activation and inflammatory responses in IBD and that inhibition of ROCK2 activity might serve as a novel therapeutic approach in the management of IBD.

Keywords: IBD; ROCK2; Slx-2119; T cell differentiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Cell Differentiation
  • Cells, Cultured
  • Colitis / chemically induced
  • Colitis / immunology*
  • Disease Models, Animal
  • Female
  • Humans
  • Inflammation / immunology*
  • Inflammatory Bowel Diseases / immunology*
  • Intestinal Mucosa / immunology*
  • Lymphocyte Activation
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Middle Aged
  • Signal Transduction
  • T-Lymphocytes, Regulatory / immunology*
  • Th1 Cells / immunology*
  • Th17 Cells / immunology*
  • Young Adult
  • rho-Associated Kinases / metabolism*

Substances

  • ROCK2 protein, human
  • Rock2 protein, mouse
  • rho-Associated Kinases