The role of p38 mitogen-activated protein kinase in regulating interleukin-10 gene expression in Burkitt's lymphoma cell lines.
In malignant B lymphoma cells interleukin-10 (IL-10) expression is frequently upregulated. This effect is thought to support to the malignant transformation of these cells and to be a potential target for pharmacotherapy. To define better the mechanism for upregulation of the IL-10 gene, we tested the association between IL-10 and p38 mitogen-activated protein kinase (MAPK) in several Epstein-Barr virus (EBV) infected and non-infected Burkitt's lymphoma (BL) cell lines. The all BL cell lines expressed IL-10 and IL-10 receptor mRNAs, and produced IL-10. p38 MAPK was constitutively phosphorylated in the cytoplasm of the BL cell lines. We further analyzed molecular effects of p38 MAPK on IL-10 expression in Akata cells. Exogenous IL-10 lead rapidly to phosphorylation of Jak1 and Tyk2 as transducers of signals of IL-10, and promoted growth of Akata cells in a dose-dependent manner. The phosphorylation of cytoplasmic p38 MAPK in Akata cells was reduced by the serine/threonine kinase inhibitor, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H7). A specific inhibitor of p38 MAPK, SB203580, blocked simultaneously STAT3 DNA-binding activity, and IL-10 mRNA expression, IL-10 production, and then the cell growth was inhibited. These results indicate that the p38 MAPK pathway is functionally linked to IL-10 gene expression and supports the view that the constitutive activation of cytoplasmic p38 MAPK in BL cells is a step in the upregulation of IL-10 gene expression and lymphomagenesis.
Horie
Kazutaka
K
Division of Biosignaling, Department of Biomedical Sciences, School of Life Science, Faculty of Medicine, Tottori University, Japan.
Ohashi
Makoto
M
Satoh
Yukio
Y
Sairenji
Takeshi
T
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000494:pharmacology; D002051:Burkitt Lymphoma / Q000378:metabolism*; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D016753:Interleukin-10 / Q000096:biosynthesis*; D053613:Janus Kinase 1 / Q000378:metabolism; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D053701:Receptors, Interleukin-10 / Q000096:biosynthesis; D053634:TYK2 Kinase / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*
D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D012333:RNA, Messenger; D053701:Receptors, Interleukin-10; D016753:Interleukin-10; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; C507904:JAK1 protein, human; D053613:Janus Kinase 1; D053634:TYK2 Kinase; C070139:TYK2 protein, human; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580