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Am J Pathol. 2013 May;182(5):1617-28. doi: 10.1016/j.ajpath.2013.01.028. Epub 2013 Mar 13.

Knockout of Ste20-like proline/alanine-rich kinase (SPAK) attenuates intestinal inflammation in mice.

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  • 1Department of Biology, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, USA.

Abstract

Inflammatory bowel diseases are characterized by epithelial barrier disruption and alterations in immune regulation. Ste20-like proline/alanine-rich kinase (SPAK) plays a role in intestinal inflammation, but the underlying mechanisms need to be defined. Herein, SPAK knockout (KO) C57BL/6 mice exhibited significant increases in intestinal transepithelial resistance, a marked decrease in paracellular permeability to fluorescence isothiocyanate-dextran, and altered apical side tight junction sodium ion selectivity, compared with wild-type mice. Furthermore, the expression of junction protein, claudin-2, decreased. In contrast, expressions of occludin, E-cadherin, β-catenin, and claudin-5 increased significantly, whereas no obvious change of claudin-1, claudin-4, zonula occludens protein 1, and zonula occludens protein 2 expressions was observed. In murine models of colitis induced by dextran sulfate sodium and trinitrobenzene sulfuric acid, KO mice were more tolerant than wild-type mice, as demonstrated by colonoscopy features, histological characteristics, and myeloperoxidase activities. Consistent with these findings, KO mice showed increased IL-10 levels and decreased proinflammatory cytokine secretion, ameliorated bacterial translocation on treatment with dextran sulfate sodium, and regulation of with no lysine (WNK) kinase activity. Together, these features may reduce epithelial permeability. In conclusion, SPAK deficiency increases intestinal innate immune homeostasis, which is important for control or attenuation of pathological responses in inflammatory bowel diseases.

Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

PMID:
23499375
[PubMed - indexed for MEDLINE]
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