Involvement of Proton-Sensing TDAG8 in Extracellular Acidification-Induced Inhibition of Proinflammatory Cytokine Production in Peritoneal Macrophages
Involvement of Proton-Sensing TDAG8 in Extracellular Acidification-Induced Inhibition of Proinflammatory Cytokine Production in Peritoneal Macrophages
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DOI：
10.4049/jimmunol.0803466
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发表时间：
2009-03-01
影响因子：
4.4
通讯作者：
Okajima, Fumikazu
中科院分区：
文献类型：
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作者：
Mogi, Chihiro;Tobo, Masayuki;Okajima, Fumikazu
在小鼠腹膜巨噬细胞中，细胞外酸化抑制lps诱导的tnf - α蛋白产生，这与抑制tnf - α mRNA表达有关。G(s)蛋白偶联受体激动剂前列腺素E-1和异丙肾上腺素也能抑制lps诱导的细胞因子的产生。在OGR1家族质子感应gtp结合调节蛋白偶联受体中，TDAG8、OGR1、抗G2A在细胞中表达。酸性pH对TDAG8（TP/TP）小鼠巨噬细胞tnf - α产生的抑制作用显著减弱，而对OGR1（geo/geo）小鼠巨噬细胞的抑制作用则不明显。此外，TDAG8特异性而非G2A特异性的小干扰RNA明显减弱了酸化诱导的对tnf - α产生的抑制。另一方面，TDAG8的下调或缺乏几乎不影响前列腺素E-1或异丙肾上腺素诱导的作用。脂多糖诱导的IL-6的产生也被胞外酸化以一种对TDAG8表达敏感的方式抑制。酸性ph诱导的对细胞因子产生的抑制作用被G(s)蛋白特异性的小干扰RNA或蛋白激酶a （PKA）特异性抑制剂H89显著逆转。事实上，pka特异性cAMP衍生物抑制lps诱导的细胞因子产生。此外，酸化以tdag8特异性的方式诱导cAMP积累。我们得出结论，TDAG8至少在一定程度上通过小鼠巨噬细胞G(s)蛋白/cAMP/PKA信号通路介导细胞外酸化诱导的促炎细胞因子产生的抑制。免疫学杂志，2009,32(2):343 - 351。
Extracellular acidification inhibited LPS-induced TNF-alpha protein production, which was associated with an inhibition of TNF-alpha mRNA expression, in mouse peritoneal macrophages. The LPS-induced cytokine production was also inhibited by G(s) protein-coupled receptor agonists prostaglandin E-1 and isoproterenol. Among OGR1 family proton-sensing GTP-binding regulatory protein-coupled receptors, TDAG8, OGR1, anti G2A are expressed in the cells. The inhibitory action by acidic pH on TNF-alpha production was significantly attenuated in macrophages from TDAG8(TP/TP) mice but not in those from OGR1(geo/geo) mice. Moreover, small interfering RNA specific to TDAG8, but not to G2A, clearly attenuated the acidification-induced inhibition of TNF-alpha production. On the other hand, the down-regulation or deficiency of TDAG8 hardly affected prostaglandin E-1- or isoproterenol-induced actions. LPS-induced IL-6 production was also inhibited by extracellular acidification in a manner that was sensitive to TDAG8 expression. The acidic pH-induced inhibitory action on the cytokine production was significantly reversed either by a small interfering RNA specific to G(s) proteins or by a protein kinase A (PKA)-specific inhibitor H89. Indeed, a PKA-specific cAMP derivative inhibited LPS-induced cytokine production. Moreover, acidification induced cAMP accumulation in a TDAG8-specific way. We conclude that TDAG8, at least partly, mediates the extracellular acidification-induced inhibition of proinflammatory cytokine production through the G(s) protein/cAMP/PKA signaling pathway in mouse macrophages. The Journal of Immunology, 2009, 182: 3243-3251.