Involvement of proton-sensing TDAG8 in extracellular acidification-induced inhibition of proinflammatory cytokine production in peritoneal macrophages

Chihiro Mogi, Masayuki Tobo, Hideaki Tomura, Naoya Murata, Xiao Dong He, Koichi Sato, Takao Kimura, Tamotsu Ishizuka, Takehiko Sasaki, Takashi Sato, Yasuyuki Kihara, Satoshi Ishii, Akihiro Harada, Fumikazu Okajima

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103 Citations (Scopus)

Abstract

Extracellular acidification inhibited LPS-induced TNF-α protein production, which was associated with an inhibition of TNF-α mRNA expression, in mouse peritoneal macrophages. The LPS-induced cytokine production was also inhibited by Gs proteincoupled 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-α production was significantly attenuated in macrophages from TDAG8 Tp/Tp mice but not in those from OGR1geo/geo mice. Moreover, small interfering RNA specific to TDAG8, but not to G2A, clearly attenuated the acidification-induced inhibition of TNF-α production. On the other hand, the down-regulation or deficiency of TDAG8 hardly affected prostaglandin E1- or isoproterenolinduced 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 Gs 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 Gs protein/cAMP/PKA signaling pathway in mouse macrophages.

Original languageEnglish
Pages (from-to)3243-3251
Number of pages9
JournalJournal of Immunology
Volume182
Issue number5
DOIs
Publication statusPublished - 1 Mar 2009

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    Mogi, C., Tobo, M., Tomura, H., Murata, N., He, X. D., Sato, K., Kimura, T., Ishizuka, T., Sasaki, T., Sato, T., Kihara, Y., Ishii, S., Harada, A., & Okajima, F. (2009). Involvement of proton-sensing TDAG8 in extracellular acidification-induced inhibition of proinflammatory cytokine production in peritoneal macrophages. Journal of Immunology, 182(5), 3243-3251. https://doi.org/10.4049/jimmunol.0803466