Signal transduction pathway(s) involved in phorbol ester and autocrine induction of interleukin-1 alpha mRNA in murine keratinocytes.
We investigated the signal transduction pathways leading to the 12-O-tetradecanoylphorbol-13-acetate (TPA)- and interleukin-1 alpha (IL-1)-induced IL-1 alpha mRNA in mouse keratinocytes. Induction of IL-1 alpha mRNA by TPA or IL-1 alpha was followed by increases in cell-associated IL-1 alpha protein measured by enzyme-linked immunosorbent assay. Although protein kinase C (PKC) was involved in TPA-induced IL-1 alpha mRNA, down-regulation of PKC did not block the induction of this gene by TPA. The autocrine induction of IL-1 alpha was not mediated through PKC or cAMP. IL-1 alpha did activate mitogen-activated protein kinase. Genistein, a tyrosine kinase inhibitor, blocked both IL-1 alpha-induced mitogen-activated protein kinase activation as well as IL-1 alpha mRNA expression. Genistein, at an unsaturating dose, plus a serine/threonine kinase inhibitor, H7, completely blocked the autocrine induction of IL-1 alpha suggesting that expression of this gene is regulated by tyrosine kinase(s) in combination or independently with serine/threonine kinase(s). In addition, both TPA and IL-1 alpha caused increases not only in the phosphorylation of c-Jun and c-Fos protein but also in the transactivating activity of AP-1 nuclear transcription factor. Neither TPA nor IL-1 alpha induced NF-kappa B binding activity, as assessed by electrophoretic mobility shift analysis. This study suggests that the activation of AP-1 may be a common event through which TPA and IL-1 alpha induce IL-1 alpha mRNA.
Lee
W Y
WY
Department of Pharmacology/Toxicology, College of Pharmacy, University of Texas, Austin 78712.
Butler
A P
AP
Locniskar
M F
MF
Fischer
S M
SM
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000818:Animals; D002478:Cells, Cultured; D004789:Enzyme Activation; D005786:Gene Expression Regulation / Q000187:drug effects; D019833:Genistein; D007375:Interleukin-1 / Q000235:genetics* / Q000378:metabolism; D007529:Isoflavones / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1; D016328:NF-kappa B / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
D007375:Interleukin-1; D007529:Isoflavones; D007546:Isoquinolines; D016328:NF-kappa B; D010879:Piperazines; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D011493:Protein Kinase C; D019950:Mitogen-Activated Protein Kinase 1; D013755:Tetradecanoylphorbol Acetate