Protein kinase C-independent activation of nuclear factor kappa B by tumor necrosis factor.
Tumor necrosis factor (TNF) is one of the few physiological inducers of the pleiotropic transcription factor NF kappa B. NF kappa B may play a central role in mediating TNF's gene regulatory action; however, the molecular mechanisms of TNF-induced NF kappa B activation are poorly understood. In this study, we demonstrate with two human leukemic cell lines, K562 and Jurkat, that TNF induces rapid and transient activation and translocation of protein kinase C (PK-C) from the cytosol to the membranes, which is followed by the emergence of kappa B-binding activity. In order to investigate whether TNF-mediated PK-C activation can be linked to induction of NF kappa B, we tried to block TNF action by use of various protein kinase C inhibitors as well as down-regulation of PK-C. Preincubation of Jurkat cells with protein kinase inhibitor H7 or staurosporine blocked PK-C activation by either TNF or phorbol 12-myristate 12-acetate (PMA). This pretreatment regimen completely inhibited NF kappa B activation by PMA. In contrast, TNF's ability to induce NF kappa B remained unaffected. In addition, NF kappa B was TNF-inducible in Jurkat cells depleted for PK-C by long-term exposure to high dose phorbol ester. The data indicate that PK-C is not required for NF kappa B activation by TNF and imply a novel, PK-C-independent mechanism of physiological NF kappa B activation.
Meichle
A
A
Klinische Arbeitsgruppe der Max-Planck-Gesellschaft, Göttingen, Federal Republic of Germany.
Schütze
S
S
Hensel
G
G
Brunsing
D
D
Krönke
M
M
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000470:Alkaloids / Q000494:pharmacology; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D004279:DNA, Viral / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation; D004742:Enhancer Elements, Genetic; D004789:Enzyme Activation / Q000187:drug effects; D006183:H-2 Antigens / Q000235:genetics; D015497:HIV-1 / Q000235:genetics; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D007938:Leukemia; D008969:Molecular Sequence Data; D016328:NF-kappa B; D015240:Phorbol 12,13-Dibutyrate; D010879:Piperazines / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000470:Alkaloids; D004279:DNA, Viral; D004268:DNA-Binding Proteins; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D007546:Isoquinolines; D016328:NF-kappa B; D010879:Piperazines; D011994:Recombinant Proteins; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D015240:Phorbol 12,13-Dibutyrate; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D011493:Protein Kinase C; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate