Involvement of CYP1B1 in interferon gamma-induced alterations of epithelial barrier integrity

Abstract

BACKGROUND AND PURPOSECYP1B1 and CYP1A1 are important extra-hepatic cytochromes, expressed in the colon and involved in the metabolism of dietary constituents and exogenous compounds. CYP1B1 expression is increased by pro-inflammatory cytokines, and it has been recently implicated in regulation of blood brain barrier function. We investigated its involvement in the increased permeability of the intestinal epithelial barrier observed in inflammatory conditions.EXPERIMENTAL APPROACHEpithelial monolayers formed by human T84 colon carcinoma cells cultured on transwells, were disrupted by incubation with IFN gamma (10 ng.mL(-1)). Monolayer integrity was measured using transepithelial electrical resistance. CYP1A1 and CYP1B1 inhibitors or inducers were applied apically. Potential mechanisms of action were investigated using RT-qPCR.KEY RESULTSIFN gamma disrupts the barrier integrity of the T84 monolayers and increases CYP1B1 and HIF1 alpha mRNA expression. CYP1B1 induction is inhibited by the NF-kappa B inhibitor ammonium pyrrolidinedithiocarbamate (100 mu M) but not by the HIF1 alpha inhibitor 3-(5-hydroxymethyl-2-furyl)-1-benzyl indazole (50 mu M). Inhibition of CYP1B1 with the selective inhibitor 2,4,3,5-tetramethoxystilbene (100 nM) partly reverses the effects of IFN gamma on epithelial permeability.CONCLUSIONS AND IMPLICATIONSThese data suggest that increased expression of CYP1B1 is involved in the effects of IFN gamma on epithelial permeability. Inhibition of CYP1B1 counteracts the alterations of epithelial barrier integrity induced by IFN gamma and could thus have a therapeutic potential in disorders of intestinal permeability associated with inflammation.

Published in

British Journal of Pharmacology
2018, volume: 175, number: 6, pages: 877-890
Publisher: WILEY

SLU Authors

• Gouveia, Sandra

  • Department of Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences
    
  • Umeå University

UKÄ Subject classification

Pharmacology and Toxicology

Publication identifier

• DOI: https://doi.org/10.1111/bph.14122

Permanent link to this page (URI)

https://res.slu.se/id/publ/94394