VCAM-1 upregulation via PKCdelta-p38 kinase-linked cascade mediates the TNF-alpha-induced leukocyte adhesion and emigration in the lung airway epithelium.
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 PKCdelta 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 in a p38 kinase-dependent manner; also, TNF-alpha-induced p38 kinase activation was blocked by inhibition of PKCdelta, suggesting that p38 kinase is apparently situated downstream of PKCdelta in the TNF-alpha-signaling pathway to VCAM-1 expression. Notably, inhibition of the PKCdelta-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. Together, these findings indicate that signaling via PKCdelta-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.
School of Life Sciences and Biotechnology, Korea University, 5-1 Anam-dong, Sungbuk-gu, Seoul, 136-701, Korea.
Chang-Hoon
CH
Woo
Jae-Hyang
JH
Lim
Jae-Hong
JH
Kim
D000098:Acetophenones / Q000494:pharmacology; D001578:Benzopyrans / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000502:physiology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007322:Instillation, Drug; D007527:Isoenzymes / Q000378:metabolism; D007962:Leukocytes / Q000502:physiology*; D008168:Lung / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism*; D051745:Protein Kinase C-delta; D011725:Pyridines / Q000494:pharmacology; D014132:Trachea; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000494:pharmacology*; D015854:Up-Regulation; D019010:Vascular Cell Adhesion Molecule-1 / Q000187:drug effects / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D000098:Acetophenones; D001578:Benzopyrans; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007527:Isoenzymes; D016328:NF-kappa B; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; C085746:rottlerin; C497258:PRKCD protein, human; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580