Cyclosporine A enhances leukocyte binding by human intestinal microvascular endothelial cells through inhibition of p38 MAPK and iNOS: Paradoxical proinflammatory effect on the microvascular endothelium

Parvaneh Rafiee, Christopher P. Johnson, Mona S. Li, Hitoshi Ogawa, Jan Heidemann, Pamela J. Fisher, Thomas H. Lamirand, Mary F. Otterson, Keith T. Wilson, David G. Binion

    Research output: Contribution to journalArticlepeer-review

    59 Citations (Scopus)

    Abstract

    The calcineurin inhibitor cyclosporine A (CsA) modulates leukocyte cytokine production but may also effect nonimmune cells, including microvascular endothelial cells, which regulate the inflammatory process through leukocyte recruitment. We hypothesized that CsA would promote a proinflammatory phenotype in human intestinal microvascular endothelial cells (HIMEC), by inhibiting inducible nitric-oxide synthase (iNOS, NOS2)-derived NO, normally an important mechanism in limiting endothelial activation and leukocyte adhesion. Primary cultures of HIMEC were used to assess CsA effects on endothelial activation, leukocyte interaction, and the expression of iNOS as well as cell adhesion molecules. CsA significantly increased leukocyte binding to activated HIMEC, but paradoxically decreased endothelial expression of cell adhesion molecules (E-selectin, intercellular adhesion molecule 1, and vascular cell adhesion molecule-1). In contrast, CsA completely inhibited the expression of iNOS in tumor necrosis factor-α/lipopolysaccharide-activated HIMEC. CsA blocked p38 MAPK phosphorylation in activated HIMEC, a key pathway in iNOS expression, but failed to inhibit NFκB activation. These studies demonstrate that CsA exerts a proinflammatory effect on HIMEC by blocking iNOS expression. CsA exerts a proinflammatory effect on the microvascular endothelium, and this drug-induced endothelial dysfunction may help explain its lack of efficacy in the long-term treatment of chronically active inflammatory bowel disease.

    Original languageEnglish
    Pages (from-to)35605-35615
    Number of pages11
    JournalJournal of Biological Chemistry
    Volume277
    Issue number38
    DOIs
    Publication statusPublished - 2002 Sep 20

    ASJC Scopus subject areas

    • Biochemistry

    Fingerprint

    Dive into the research topics of 'Cyclosporine A enhances leukocyte binding by human intestinal microvascular endothelial cells through inhibition of p38 MAPK and iNOS: Paradoxical proinflammatory effect on the microvascular endothelium'. Together they form a unique fingerprint.

    Cite this