title: Involvement of proton-sensing TDAG8 in extracellular acidification-induced inhibition of proinflammatory cytokine production in peritoneal macrophages.
abstract: 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, and 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.
authors.affiliation: Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Mogi
authors.forename: Masayuki
authors.initials: M
authors.lastname: Tobo
authors.forename: Hideaki
authors.initials: H
authors.lastname: Tomura
authors.forename: Naoya
authors.initials: N
authors.lastname: Murata
authors.forename: Xiao-dong
authors.initials: XD
authors.lastname: He
authors.forename: Koichi
authors.initials: K
authors.lastname: Sato
authors.forename: Takao
authors.initials: T
authors.lastname: Kimura
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Ishizuka
authors.forename: Takehiko
authors.initials: T
authors.lastname: Sasaki
authors.forename: Takashi
authors.initials: T
authors.lastname: Sato
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Kihara
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ishii
authors.forename: Akihiro
authors.initials: A
authors.lastname: Harada
authors.forename: Fumikazu
authors.initials: F
authors.lastname: Okajima
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D005110:Extracellular Space / Q000276:immunology / Q000378:metabolism*; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000502:physiology; D006863:Hydrogen-Ion Concentration; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D011522:Protons; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology
chemical_list: D016207:Cytokines; C513334:GPR65 protein, human; C525539:GPR68 protein, mouse; D018836:Inflammation Mediators; D011522:Protons; D043562:Receptors, G-Protein-Coupled; D017868:Cyclic AMP-Dependent Protein Kinases; D019205:GTP-Binding Protein alpha Subunits, Gs