IL-17A signaling in colonic epithelial cells inhibits pro-inflammatory cytokine production by enhancing the activity of ERK and PI3K.

Xiaoqin Guo,Zhi Zhao,Tingting Zhou,Yan Li,Xingwei Jiang,Renxi Wang,Xiaoling Lang,Yueling Guo,Yanhua Lin,Beifen Shen,Lingyun Ma,Chunmei Hou,Guojiang Chen,Yan Xiao,He Xiao,Gencheng Han,Jiannan Feng,Emiko Mizoguchi

doi:10.1371/journal.pone.0089714

Abstract

Our previous data suggested that IL-17A contributes to the inhibition of Th1 cell function in the gut. However, the underlying mechanisms remain unclear. Here we demonstrate that IL-17A signaling in colonic epithelial cells (CECs) increases TNF-α-induced PI3K-AKT and ERK phosphorylation and inhibits TNF-α induced expression of IL-12P35 and of a Th1 cell chemokine, CXCL11 at mRNA level. In a co-culture system using HT-29 cells and PBMCs, IL-17A inhibited TNF-ãinduced IL-12P35 expression by HT-29 cells and led to decreased expression of IFN-γ and T-bet by PBMCs. Finally, adoptive transfer of CECs from mice with Crohn's Disease (CD) led to an enhanced Th1 cell response and exacerbated colitis in CD mouse recipients. The pathogenic effect of CECs derived from CD mice was reversed by co-administration of recombinant IL-17A. Our data demonstrate a new IL-17A-mediated regulatory mechanism in CD. A better understanding of this pathway might shed new light on the pathogenesis of CD.

Highlights

Crohn’s disease (CD) and ulcerative colitis (UC) are two forms of inflammatory bowel disease (IBD) in man
IL-17A signaling in human HT-29 colonic epithelia cells inhibits TNF-a-induced expression of CXCL11 and IL12P35 mRNA by enhancing phosphorylation of AKT, ERK, and CEBP/b
To test whether, and if so, how the increased IL-17A expression was responsible for inhibition of Th1 cell function in IBD, we used the human colonic epithelial cell line HT-29 cells, as we have found that the expression of IL-17A in and IL-17 receptor (IL-17R) on colonic epithelial cells (CECs) cells is significantly increased in mice with trinitrobenzene sulfonic acid (TNBS)-induced colitis, which is an animal model of Crohn’s disease (CD)

Summary

Introduction

Crohn’s disease (CD) and ulcerative colitis (UC) are two forms of inflammatory bowel disease (IBD) in man. The etiology of IBD remains unclear, but evidence indicates that it results from an interaction between genetic and environmental factors, which eventually lead to an excessive and poorly controlled mucosal inflammatory response directed against components of the normal microflora and mucosal constituents of the gut [1,2]. Antibody against TNF-a attenuates colitis in IBD patients, but more than one third of IBD patients do not respond to anti-TNF-a therapy [5,6]. These observations suggest the need to identify novel targets for therapeutic intervention in IBD

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