Protein kinase C-z mediates TNF-a-induced ICAM-1 gene transcription in endothelial cells

Rahman, Arshad, Khandaker N. Anwar, and Asrar B. Malik. Protein kinase C-z mediates TNF-a-induced ICAM-1 gene transcription in endothelial cells. Am J Physiol Cell Physiol 279: C906–C914, 2000.—We addressed the role of protein kinase C (PKC) isozymes in mediating tumor necrosis factor-a (TNF-a)-induced oxidant generation in endothelial cells, a requirement for nuclear factor-kB (NF-kB) activation and intercellular adhesion molecule-1 (ICAM-1) gene transcription. Depletion of the conventional (c) and novel (n) PKC isozymes following 24 h exposure of human pulmonary artery endothelial (HPAE) cells with the phorbol ester, phorbol 12myristate 13-acetate (500 nM), failed to prevent TNF-a-induced oxidant generation. In contrast, inhibition of PKC-z synthesis by the antisense oligonucleotide prevented the oxidant generation following the TNF-a stimulation. We observed that PKC-z also induced the TNF-a-induced NF-kB binding to the ICAM-1 promoter and the resultant ICAM-1 gene transcription. We showed that expression of the dominant negative mutant of PKC-z prevented the TNF-a-induced ICAM-1 promoter activity, whereas overexpression of the wild-type PKC-z augmented the response. These data imply a critical role for the PKC-z isozyme in regulating TNF-a-induced oxidant generation and in signaling the activation of NF-kB and ICAM-1 transcription in endothelial cells.