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Am J Physiol Lung Cell Mol Physiol (October 15, 2004). doi:10.1152/ajplung.00105.2004
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Submitted on March 22, 2004
Accepted on October 13, 2004

VCAM-1 up-regulation via PKC-{delta}-p38 kinase-linked cascade mediates the TNF{alpha}-induced leukocyte adhesion and emigration in the lung airway epithelium

Chang-Hoon Woo1, Jae-Hyang Lim1, and Jae-Hong Kim1*

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

* To whom correspondence should be addressed. E-mail: jhongkim{at}korea.ac.kr.

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




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