Cyclosporine A Enhances Leukocyte Binding by Human Intestinal Microvascular Endothelial Cells through Inhibition of p38 MAPK and iNOS

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

Immunomodulatory benefits of cyclosporine A in inflammatory bowel disease

“…Transcriptional factors [i.e., nuclear factor kappa B (NF-κB)] are involved in the expression of endothelial adhesion molecules [4]. In this regard, CYA attenuates adhesion interaction and transendothelial migration and infiltration of neutrophils by decreasing endothelial expression of cell adhesion molecules (E-selectin, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1) and inhibiting the antiapoptotic NF-κB, a central transcription factor mediating inflammatory injury [16]. CYA causes consistent inhibition of chemotactic migration, superoxide generation, and chemokine (IL-8) production by neutrophils in a dose-dependent manner.…”

Effect of curcumin on p38MAPK expression in DSS-induced murine ulcerative colitis

“…Therefore, the p38 MAPK signal transduction pathway plays an important role in the inflammatory response. Rafiee et al (2002) found that p-p38MAPK was higher in IBD patients than in normal people, and positively correlated with the degree of intestinal inflammation (Zhao et al, 2011). Waetzig et al (2002) found that during IBD intestinal epithelial injury, the activity of p38MAPK was significantly increased, and revealed that by tissue immunohistochemistry high p38MAPK expression in macrophages and neutrophils of the intestinal lamina propria.…”

“…It could be activated by various cytokines (TNF-a, IL-1), lipopolysaccharide, stress stimuli (heat shock, hyperosmolar injury, ischemia -reperfusion) (Rafiee et al, 2002;Jameel et al, 2009). A number of studies have shown that cells exposed to the above stimuli could activate p38MAPK, which would then regulate the inflammatory response by the following means.…”

Methotrexate inhibits integrin adhesion molecules in the mouse model of pleurisy induced by carrageenan

“…There are few studies demonstrating the inhibitory effect of immunosuppressor drugs upon leukocyte migration. In vitro studies have shown that cyclosporin A (CLPA) inhibited intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1, (VCAM-1), E-selectin, P-selectin, platelet/endothelial cell adhesion molecule-1 (PECAM-1) and the L-selectin ligand CD34 in human endothelial cells (Markovic et al, 2002;Rafiee et al, 2002;Zhou et al, 2004). CLPA reduced also endothelial and keratinocyte ICAM-1 expression in patients with psoriasis (Servitje et al, 1996).…”