Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Contributions of HO-1-Dependent MAPK to Regulating Intestinal Barrier Disruption

  • Zhang, Zhenling (Department of Gastroenterology, the First Affiliated Hospital of Dalian Medical University) ;
  • Zhang, Qiuping (Department of Pathology, the First Affiliated Hospital of Dalian Medical University) ;
  • Li, Fang (Department of Immunology, Dalian Medical University) ;
  • Xin, Yi (Department of Biochemistry and Molecular Biology, Dalian Medical University) ;
  • Duan, Zhijun (Department of Gastroenterology, the First Affiliated Hospital of Dalian Medical University)
  • Received : 2020.06.28
  • Accepted : 2020.08.14
  • Published : 2021.03.01
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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

References

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