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VCAM-1 upregulation via PKC-p38 kinase-linked cascade mediates the TNF--induced leukocyte adhesion and emigration in the lung airway epithelium

School of Life Sciences and Biotechnology, Korea University, Seoul, Korea

Submitted 22 March 2004 ; accepted in final form 13 October 2004

Vascular cell adhesion molecule (VCAM)-1 plays a central role in the recruitment of inflammatory cells, and its expression is rapidly induced by proinflammatory cytokines such as TNF-. In the present study, we show that pretreatment with rottlerin, a specific inhibitor of protein kinase C (PKC)-, or transient transfection with antisense PKC oligonucleotides significantly inhibits TNF--induced expression of VCAM-1, but not of intercellular adhesion molecule (ICAM)-1 in human lung epithelium A549 cells. In addition, TNF- was shown to induce the expression of VCAM-1 in a p38 kinase-dependent manner; also, TNF--induced p38 kinase activation was blocked by inhibition of PKC, suggesting that p38 kinase is apparently situated downstream of PKC in the TNF--signaling pathway to VCAM-1 expression. Notably, inhibition of the PKC-p38 kinase cascade also attenuated the TNF--induced adhesion of neutrophils to lung epithelium and the trafficking of leukocytes across the epithelium into the airway lumen in vivo. Together, these findings indicate that signaling via PKC-p38 kinase-linked cascade specifically induces expression of VCAM-1 in lung epithelium in response to TNF- and that this effect is both functionally and clinically significant.

lung inflammation; protein kinase C-; vascular cell adhesion molecule-1

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