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Thromboxane A₂ Promotes Interleukin-6 Biosynthesis Mediated by an Activation of Cyclic AMP-Response Element-Binding Protein in 1321N1 Human Astrocytoma Cells

Department of Cellular Signaling, 21st COE program "CRESCENDO", Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan (Y.O., N.N.); and Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan (H.K.)

1321N1 human astrocytoma cells express thromboxane A₂ (TXA₂) receptors (TP). However, physiological consequences of TXA₂ signaling in glial cells remain unclear. Herein, we show that TXA₂ promotes interleukin-6 (IL-6) biosynthesis in glial cells. A TP agonist, 9,11-dideoxy-9,11-methanoepoxy-prosta-5Z,13E-dien-1-oic acid (U46619), enhanced IL-6 production in both 1321N1 cells and cultured mouse astrocytes. It has been shown that IL-6 gene expression is regulated by various transcription factors. Among them, we found a significant increase in cyclic AMP-response element-binding protein (CREB) activity with its phosphorylation at Ser133 by U46619 in 1321N1 cells. Although U46619 increased IL-6 promoter activity, a mutation at cyclic AMP-response element (CRE) on the promoter clearly suppressed the effect, suggesting that CRE is involved in U46619-induced IL-6 expression. Furthermore, both CREB and IL-6 promoter activities were suppressed by SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole], a p38 mitogen-activated protein kinase (MAPK) inhibitor, and H89 [N-[2-(4-bromocinnamylamino)-ethyl]-5-isoquinoline], a protein kinase A (PKA) inhibitor, indicating involvements of p38 MAPK and PKA in CREB activation and IL-6 expression. To determine which G-proteins are implicated in the U46619-induced IL-6 synthesis, the interfering mutants of G_q, G₁₂, or G₁₃ by were overexpressed in 1321N1 cells adenoviral approach. It is noteworthy that the G_q or G₁₃ mutant blocked the IL-6 production by U46619. The constitutively active mutant of G_q, G₁₂, or G₁₃ enhanced IL-6 production, indicating that G_q and G₁₃ were involved in U46619-induced IL-6 production. In conclusion, TXA₂ enhances the IL-6 biosynthesis via the PKA p38 MAPK/CREB pathway in 1321N1 cells. IL-6 induction depends on G_q and G₁₃ as well. This is the first report showing TP-mediated IL-6 production in glial cells.

Address correspondence to: Dr. Yutaro Obara, Department of Cellular Signaling, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan. E-mail: obaray{at}mail.pharm.tohoku.ac.jp

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