Biomolecules & Therapeutics  https://doi.org/10.4062/biomolther.2020.112
Contributions of HO-1-Dependent MAPK to Regulating Intestinal Barrier Disruption
Zhenling Zhang1, Qiuping Zhang2, Fang Li3, Yi Xin4 and Zhijun Duan1,*
1Department of Gastroenterology, the First Affiliated Hospital of Dalian Medical University, Dalian116011,
2Department of Pathology, the First Affiliated Hospital of Dalian Medical University, Dalian 116011,
3Department of Immunology, Dalian Medical University, Dalian 116044,
4Department of Biochemistry and Molecular Biology, Dalian Medical University, Dalian 116044, China
*E-mail: cathydoctor@sina.com
Tel: +86-18098875588, Fax: +86-0411-83635963
Received: June 28, 2020; Revised: August 8, 2020; Accepted: August 14, 2020; Published online: October 23, 2020.
© The Korean Society of Applied Pharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/ by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
The mitogen-activated protein kinase (MAPK) pathway controls intestinal epithelial barrier permeability by regulating tight junctions (TJs) and epithelial cells damage. Heme oxygenase-1 (HO-1) and carbon monoxide (CO) protect the intestinal epithelial barrier function, but the molecular mechanism is not yet clarified. MAPK activation and barrier permeability were studied using monolayers of Caco-2 cells treated with tissue necrosis factor α (TNF-α) transfected with FUGW-HO-1 or pLKO.1-sh-HO-1 plasmid. Intestinal mucosal barrier permeability and MAPK activation were also investigated using carbon tetrachloride (CCl4) administration with CoPP (a HO-1 inducer), ZnPP (a HO-1 inhibitor), CO releasing molecule 2 (CORM-2), or inactived-CORM-2-treated wild-type mice and mice with HO-1 deficiency in intestinal epithelial cells. TNF-α increased epithelial TJ disruption and cleaved caspase-3 expression, induced ERK, p38, and JNK phosphorylation. In addition, HO-1 blocked TNF-α-induced increase in epithelial TJs disruption, cleaved caspase-3 expression, as well as ERK, p38, and JNK phosphorylation in an HO-1-dependent manner. CoPP and CORM-2 directly ameliorated intestinal mucosal injury, attenuated TJ disruption and cleaved caspase-3 expression, and inhibited epithelial ERK, p38, and JNK phosphorylation after chronic CCl4 injection. Conversely, ZnPP completely reversed these effects. Furthermore, mice with intestinal epithelial HO-1 deficient exhibited a robust increase in mucosal TJs disruption, cleaved caspase-3 expression, and MAPKs activation as compared to the control group mice. These data demonstrated that HO-1-dependent MAPK signaling inhibition preserves the intestinal mucosal barrier integrity by abrogating TJ dysregulation and epithelial cell damage. The differential targeting of gut HO-1-MAPK axis leads to improved intestinal disease therapy.
Keywords: HO-1, Intestinal barrier function, Tight junction, MAPK, Inflammatory bowel disease


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