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-α. In the present study, we show that pretreatment with rottlerin, a specific inhibitor of protein kinase C (PKC)-δ, or transient transfection with antisense PKCδ oligonucleotides significantly inhibits TNF-α-induced expression of VCAM-1, but not of intercellular adhesion molecule (ICAM)-1 in human lung epithelium A549 cells. In addition, TNF-α was shown to induce the expression of VCAM-1 in a p38 kinase-dependent manner; also, TNF-α-induced p38 kinase activation was blocked by inhibition of PKCδ, suggesting that p38 kinase is apparently situated downstream of PKCδ in the TNF-α-signaling pathway to VCAM-1 expression. Notably, inhibition of the PKCδ-p38 kinase cascade also attenuated the TNF-α-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 PKCδ-p38 kinase-linked cascade specifically induces expression of VCAM-1 in lung epithelium in response to TNF-α and that this effect is both functionally and clinically significant.
|Journal||American Journal of Physiology - Lung Cellular and Molecular Physiology|
|Issue number||2 32-2|
|State||Published - Feb 2005|
- Lung inflammation
- Protein kinase C-δ
- Vascular cell adhesion molecule-1