Abstract
Inflammatory bowel disease is characterized by dysregulation of the mucosal immune system resulting from impaired intestinal epithelial barrier function. Protein kinase D2 has been implicated in the regulation of immune responses. The present study was to define PKD2 might affect murine colitis. Colitis was induced in wild-type mice (PKD2WT/WT) and PKD2 catalytic activity deficient mice (PKD2SSAA/SSAA) with dextran sulfate sodium. PKD2SSAA-knockin mice displayed catalytic activity deficiency and increased susceptibility to DSS-induced colitis with enhanced weight loss, colonic inflammation compared with PKD2WT/WT mice. Furthermore, crucial inflammatory cytokines mRNA levels in PKD2SSAA-knockin mice were higher than controls accompanied with down-regulation of ZO-1, MUC2 and intestinal barrier dysfunction. However, there were no differences in the proliferation or apoptosis of intestinal epithelial cells in PKD2SSAA-knockin mice compared with wild-type controls. In addition, PKD2 expression was repressed in patients with IBD compared with healthy controls. These studies suggested that activation of PKD2 in the colonic epithelium microenvironment may contribute to protect against DSS-induced colitis through regulation of intestinal mucosal immunity and barrier function.
Highlights
Inflammatory bowel disease (IBD), characterized by chronic and recurrent intestinal inflammation, affects over 3.6 million people worldwide[1] and is associated with high economic costs in terms of patients, healthcare and society[2]
We showed that Protein kinase D2 (PKD2) enzymatic deficiency mice exhibit elevated susceptibility to dextran sulfate sodium (DSS)-induced colitis compared with wild-type control, up-regulated expression of crucial pro-inflammatory cytokines and disrupted epithelial barrier function
Further western analysis of the activated or phosphorylated proteins level of PKD2 in different tissues of mice revealed that there was no phosphorylation on Ser[744] and Ser[748] site of activation loop of PKD2 in different tissues from PKD2SSAA/SSAA mutant mice compared with PKD2 wild type mice, demonstrating that the presence of homozygous PKD2 catalytic activity deficiency in PKD2SSAA/SSAA mutant mice (Fig. 1b)
Summary
Inflammatory bowel disease (IBD), characterized by chronic and recurrent intestinal inflammation, affects over 3.6 million people worldwide[1] and is associated with high economic costs in terms of patients, healthcare and society[2]. Genome wide association studies (GWAS) have revealed at least 163 host susceptibility loci associated with risk of IBD5, further highlighting the role of genes in this disease. The intestinal epithelium forms a protective barrier to prevent permeation of luminal microbiota and foreign antigens into mucosal tissues[6]. This barrier mainly consists of the mucus layer, tight junctions (TJs) and intestinal epithelial cells (IECs), whose integrity was largely mediated by tight junction function[7]. We showed that PKD2 enzymatic deficiency mice exhibit elevated susceptibility to dextran sulfate sodium (DSS)-induced colitis compared with wild-type control, up-regulated expression of crucial pro-inflammatory cytokines and disrupted epithelial barrier function. Our data firstly demonstrate a protective role for PKD2 in intestinal inflammation
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