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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. J Biol Chem 2002 Sep 20;277(38):35605-15

Date

07/12/2002

Pubmed ID

12110686

DOI

10.1074/jbc.M205826200

Scopus ID

2-s2.0-18544389096   57 Citations

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-alpha/lipopolysaccharide-activated HIMEC. CsA blocked p38 MAPK phosphorylation in activated HIMEC, a key pathway in iNOS expression, but failed to inhibit NFkappaB 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.

Author List

Rafiee P, Johnson CP, Li MS, Ogawa H, Heidemann J, Fisher PJ, Lamirand TH, Otterson MF, Wilson KT, Binion DG

Authors

Christopher P. Johnson MD Professor in the Surgery department at Medical College of Wisconsin
Mona S. Li MD Assistant Professor in the Surgery department at Medical College of Wisconsin
Mary F. Otterson MD Professor in the Surgery department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Base Sequence
Cell Adhesion
Cells, Cultured
Cyclosporine
DNA Primers
Endothelium, Vascular
Humans
Immunosuppressive Agents
Intestines
Leukocytes
Lipopolysaccharides
Mitogen-Activated Protein Kinases
NF-kappa B
Nitric Oxide
Nitric Oxide Synthase
Nitric Oxide Synthase Type II
Signal Transduction
Tumor Necrosis Factor-alpha
p38 Mitogen-Activated Protein Kinases
jenkins-FCD Prod-478 d1509cf07a111124a2d122fd3df854cc0b993c00