Distinct roles for p42/p44 and p38 mitogen-activated protein kinases in the induction of IL-2 by IL-1.
Interleukin 1 (IL-1) activates p42/p44 and p38 mitogen-activated protein kinases (MAP kinases) in target cells. Here we have used two specific inhibitors, PD98059 which inhibits MAP kinase kinase (MEK), and SB203580 which inhibits p38 MAP kinase to explore the involvement of these kinases in the induction of IL-2 by IL-1 in the murine thymoma cell line EL4.NOB-1. Both kinase inhibitors suppressed IL-1-stimulated IL-2 production. PD98059 blocked IL-2 mRNA accumulation and the induction of a reporter gene linked to the IL-2 promoter. In contrast, SB203580 only marginally inhibited IL-2 promoter-linked reporter gene expression and had no inhibitory effect on IL-2 mRNA levels. Neither PD98059 nor SB203580 had an inhibitory effect on NFkappaB-driven reporter gene expression in response to IL-1. Surprisingly, higher concentrations of SB203580 (30 microM) potentiated the IL-1 responses. PD98059 also inhibited induction of IL-2 by phorbol 12-myristate 13-acetate (PMA), and AP1-linked reporter gene expression in response to PMA but not IL-1. These results indicate that p42/p44 MAP kinase is involved in the regulation of IL-2 gene transcription by IL-1, whilst p38 MAP kinase has a post-transcriptional target. Additional IL-1 signalling pathways can clearly compensate for the lack of p38 MAP kinase which result in potentiation of the IL-1 responses observed at high-dose SB203580.
Matthews
J S
JS
Department of Biochemistry, Trinity College, Dublin 2, Ireland. jmtthews@hotmail.com
O'Neill
L A
LA
D000595:Amino Acid Sequence; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D017930:Genes, Reporter; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology*; D007376:Interleukin-2 / Q000096:biosynthesis* / Q000235:genetics; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology*; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000502:physiology; D047428:Protein Kinase Inhibitors; D011725:Pyridines / Q000494:pharmacology; D011817:Rabbits; D015398:Signal Transduction / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013945:Thymoma / Q000473:pathology; D013953:Thymus Neoplasms / Q000473:pathology; D018808:Transcription Factor AP-1 / Q000502:physiology; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases
D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D007375:Interleukin-1; D007376:Interleukin-2; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D018808:Transcription Factor AP-1; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D013755:Tetradecanoylphorbol Acetate; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one