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Involvement of Proton-Sensing TDAG8 in Extracellular Acidification-Induced Inhibition of Proinflammatory Cytokine Production in Peritoneal Macrophages¹

Chihiro Mogi^2,*, Masayuki Tobo^2,*, Hideaki Tomura^*, Naoya Murata^*, Xiao-dong He^*, Koichi Sato^*, Takao Kimura^*, Tamotsu Ishizuka^*, Takehiko Sasaki, Takashi Sato, Yasuyuki Kihara, Satoshi Ishii, Akihiro Harada and Fumikazu Okajima^3,*

^* Laboratory of Signal Transduction and Laboratory of Molecular Traffic, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan; Department of Microbiology, Akita University School of Medicine, Akita, Japan; and Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Tokyo, Tokyo, Japan

Extracellular acidification inhibited LPS-induced TNF- protein production, which was associated with an inhibition of TNF- mRNA expression, in mouse peritoneal macrophages. The LPS-induced cytokine production was also inhibited by G_s protein-coupled receptor agonists prostaglandin E₁ and isoproterenol. Among OGR1 family proton-sensing GTP-binding regulatory protein-coupled receptors, TDAG8, OGR1, and G2A are expressed in the cells. The inhibitory action by acidic pH on TNF- 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- production. On the other hand, the down-regulation or deficiency of TDAG8 hardly affected prostaglandin E₁- 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 costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a grants-in-aid for scientific research from the Japan Society for the Promotion of Science (to C.M., F.O., K.S., and H.T.), a grant of the Global Center of Excellence Program (to C.M. and K.S.) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and grants from ONO Medical Research Foundation (to F.O.), Yamanouchi Foundation for Research on Metabolic Disorders (to F.O.), Takeda Science Foundation (to K.S.), and a Sasakawa Scientific Research Grant from the Japan Scientific Society (to C.M).

² C.M. and M.T. contributed equally to this study.

³ Address correspondence and reprint requests to Dr. Fumikazu Okajima, Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi 371-8512, Japan. E-mail address: fokajima{at}showa.gunma-u.ac.jp

⁴ Abbreviations used in this paper: siRNA, small interfering RNA; 8-pCPT-2'-O-Me-cAMP, 8-(4-chlorophenylthio)-2'-O-methyladenosine 3',5'-cyclic monophosphate; G protein, GTP-binding regulatory protein; H89, N-(2-[p-bromocinnamylamino]ethyl)-5-isoquinolinesulfonamide; IBMX, 3-isobutyl-1-methylxanthine; pCPT-cAMP, 8-(4-chlorophenylthio)adenosine 3',5'-cyclic monophosphate; PGE₁, prostaglandin E₁; PKA, protein kinase A; poly(I:C), polyinosinic-polycytidic acid; N⁶-Ben-cAMP, N⁶-benzoyladenosine-3',5'-cyclic monophosphate; SA, splice acceptor; WT, wild type.

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