Extracellular Signal Regulated Protein Kinase and c-Jun N-Terminal Kinase are Involved in m1 Muscarinic Receptor-Enhanced Interleukin-2 Production Pathway in Jurkat Cells

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We have previously shown that m1 and m2 muscarinic receptors were expressed on human peripheral blood lymphocytes (hPBL) and that pre-stimulation of these receptors enhanced phytohemagglutinin (PHA)-induced interleukin-2 (IL-2) production. Possible intracellular signal pathways of muscarinic receptors to regulate IL-2 production were examined in human T cell line Jurkat cells. Pretreatment of the cells with muscarinic receptor agonist, oxotremorine M (Oxo-M), enhanced IL-2 production induced by phorbol 12-myristate 13-acetate (PMA)/A23187,while Oxo-M by itself did not affect IL-2 production. The enhancement of IL-2 production by Oxo-M was inhibited by 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) an m1/m3 receptor antagonist. When the cells were pretreated with AF-DX116,an m2 antagonist, the IL-2 production enhanced by Oxo-M was further stimulated. Reverse transcription-polymerase chain reaction (RT-PCR) revealed that m1 and m2 muscarinic receptors exist on Jurkat cells.The stimulation of m1 receptors enhanced the PMA/A23187-induced binding activity to AP-1 consensus sequences in IL-2 promoter and production of c-Fos and c-Jun protein. The stimulation of m1 receptors did not modify the DNA binding of NF-κB, NF-AT or Oct-1. When m1 receptors were stimulated, activities of mitogen-activated protein kinase (MAPK)/extracellular signal regulated protein kinase (ERK) and c-Jun N-terminal kinase (JNK) were increased, while p38 MAPK was not affected. Incubation with Oxo-M induced a transient increase in [Ca^<2+>]_i, which was abolished by pretreatment with 4-DAMP. Treatment with cyclosporin A markedly decreased the PMA/A23187-induced IL-2 promoter activity. This treatment, however, did not affect the enhancement of the promoter activity induced by m1 receptor stimulation.The results suggest that transcription factor AP-1 is involved in the m1 receptor-mediated enhancement of IL-2 transcript in Jurkat cells, and that pathways via MAPK/ERK and JNK, but not via p38 MAPK, are involved in the m1 receptor-mediated enhancement of IL-2 promoter activity.
公益社団法人日本薬学会の論文
2000-10-01

Extracellular Signal Regulated Protein Kinase and c-Jun N-Terminal Kinase are Involved in m1 Muscarinic Receptor-Enhanced Interleukin-2 Production Pathway in Jurkat Cells

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