title: Activation of AP-1 by IL-1 and phorbol esters in T cells. Role of protein kinase A and protein phosphatases.
abstract: We have examined the regulation of the AP-1 transcription complex in the IL-1-responsive murine T cell thymoma cell line EL-4 6.1 C10. Our results demonstrate that AP-1-mediated gene expression in T cells may be regulated by several signaling pathways and factors, including IL-1, protein kinase C, protein kinase A (PKA), and one or more serine/threonine-specific protein phosphatases. The activation of protein kinase C results in an increase in nuclear AP-1 DNA binding activity, as well as enhanced gene expression. IL-1 and agents that elevate intracellular cAMP levels do not, by themselves, induce AP-1 activation, but they synergize with phorbol esters. IL-1 and forskolin may enhance AP-1 function by different mechanisms, because forskolin enhanced gene expression without producing an increase in nuclear AP-1 DNA binding, whereas IL-1 increased AP-1-binding activity and gene expression. These observations, in conjunction with the lack of a demonstrable effect of IL-1 on cAMP production in EL-4 cells, are consistent with the view that IL-1 enhances AP-1 activation by a pathway that does not directly involve cAMP and PKA. However, the induction of AP-1 activity by IL-1 and phorbol esters is dependent upon the presence of PKA, as evidenced by the loss of AP-1 inducibility in cells transfected with a cDNA encoding protein kinase inhibitor, a specific inhibitor of PKA. The effect of protein kinase inhibitor on AP-1 activation in response to IL-1 and tetradecanoyl-phorbol-13-acetate was reversed in the presence of the serine/threonine protein phosphatase inhibitor okadaic acid. Thus, the level of AP-1 activity in T cells may be determined by the balance between the activities of several serine/threonine protein kinases and phosphatases.
authors.affiliation: Department of Microbiology and Immunology, Wake Forest University Medical Center, Winston-Salem, NC 27103.
authors.forename: M
authors.initials: M
authors.lastname: Chedid
authors.forename: B K
authors.initials: BK
authors.lastname: Yoza
authors.forename: J W
authors.initials: JW
authors.lastname: Brooks
authors.forename: S B
authors.initials: SB
authors.lastname: Mizel
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004988:Ethers, Cyclic / Q000494:pharmacology; D005786:Gene Expression Regulation; D007375:Interleukin-1 / Q000494:pharmacology*; D051379:Mice; D019319:Okadaic Acid; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000502:physiology*; D011494:Protein Kinases / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D016755:Proto-Oncogene Proteins c-jun; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D013945:Thymoma / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis*; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D004268:DNA-Binding Proteins; D004988:Ethers, Cyclic; D007375:Interleukin-1; D011518:Proto-Oncogene Proteins; D016755:Proto-Oncogene Proteins c-jun; D014157:Transcription Factors; D005576:Colforsin; D019319:Okadaic Acid; D000242:Cyclic AMP; D011494:Protein Kinases; D010749:Phosphoprotein Phosphatases; D013755:Tetradecanoylphorbol Acetate; D015056:1-Methyl-3-isobutylxanthine