| Budget Amount *help |
¥26,000,000 (Direct Cost: ¥20,000,000、Indirect Cost: ¥6,000,000)
Fiscal Year 2009: ¥12,350,000 (Direct Cost: ¥9,500,000、Indirect Cost: ¥2,850,000)
Fiscal Year 2008: ¥13,650,000 (Direct Cost: ¥10,500,000、Indirect Cost: ¥3,150,000)
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| Research Abstract |
We analyzed the physiological function of sphingosine-1-phoshate (S1P) and S1P receptors in the intestinal epithelial cells. It was observed that S1P_2 receptor is highly expressed in the intestinal epithelial cells (IECs). Then we analyzed the effect of S1P on immune function of IECs. Treatment of mouse IEC line with S1P additionally up-regulated the mRNA expression and secretion of IL-6 induced by Pam3CSK4 (TLR1/2 ligand) and also TLR2, 5, 7 ligands. S1P and S1P_2 agonist induced the IL-6 secretion and mRNA expression in the Pam3CSK4-treated IEC line and this effect was completely abolished by treatment with S1P_2 antagonist (JTE013). Luciferase reporter assay indicated that treatment with Pam3CSK4 induced the promoter activity of the murine IL-6 gene (from -375 to +15), and additional treatment with S1P_2 agonist further induced the IL-6 promoter activity. cAMP responsive element (CRE : from -183 to -175) on the murine IL-6 promoter was necessary for the induction by S1P_2 agonist. The siRNA targeting GNAS and PKA inhibitor (H-89) abolished the enhancement of IL-6 secretion by S1P and S1P_2 agonist in the Pam3CSK4-treated IECs. The expression level of IL-6 mRNA in the mouse ileum induced by Pam3CSK4 was significantly blocked by treatment with JTE013. These results suggest that S1P regulates cytokine production, especially IL-6, in IECs via S1P_2 and cAMP signaling pathway.
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