RRC ID 44863
Author Jin Y, Sato K, Tobo A, Mogi C, Tobo M, Murata N, Ishii S, Im DS, Okajima F.
Title Inhibition of interleukin-1β production by extracellular acidification through the TDAG8/cAMP pathway in mouse microglia.
Journal J Neurochem
Abstract Interleukin-1β (IL-1β) is released from activated microglia and involved in the neurodegeneration of acute and chronic brain disorders, such as stroke and Alzheimer's disease, in which extracellular acidification has been shown to occur. Here, we examined the extracellular acidic pH regulation of IL-1β production, especially focusing on TDAG8, a major proton-sensing G-protein-coupled receptor, in mouse microglia. Extracellular acidification inhibited lipopolysaccharide -induced IL-1β production, which was associated with the inhibition of IL-1β cytoplasmic precursor and mRNA expression. The IL-1β mRNA and protein responses were significantly, though not completely, attenuated in microglia derived from TDAG8-deficient mice compared with those from wild-type mice. The acidic pH also stimulated cellular cAMP accumulation, which was completely inhibited by TDAG8 deficiency. Forskolin and a cAMP derivative, which specifically stimulates protein kinase A (PKA), mimicked the proton actions, and PKA inhibitors reversed the acidic pH-induced IL-1β mRNA expression. The acidic pH-induced inhibitory IL-1β responses were accompanied by the inhibition of extracellular signal-related kinase and c-Jun N-terminal kinase activities. The inhibitory enzyme activities in response to acidic pH were reversed by the PKA inhibitor and TDAG8 deficiency. We conclude that extracellular acidic pH inhibits lipopolysaccharide-induced IL-1β production, at least partly, through the TDAG8/cAMP/PKA pathway, by inhibiting extracellular signal-related kinase and c-Jun N-terminal kinase activities, in mouse microglia.
Volume 129(4)
Pages 683-95
Published 2014-5-1
DOI 10.1111/jnc.12661
PMID 24447140
MeSH 1-Methyl-3-isobutylxanthine / pharmacology Animals Cells, Cultured Colforsin / pharmacology Cyclic AMP / analogs & derivatives Cyclic AMP / pharmacology Cyclic AMP / physiology* Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors Extracellular Fluid / chemistry* Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors Extracellular Signal-Regulated MAP Kinases / physiology Gene Expression Regulation / drug effects* Hydrogen-Ion Concentration I-kappa B Proteins / metabolism Interleukin-1beta / biosynthesis* Interleukin-1beta / genetics JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors JNK Mitogen-Activated Protein Kinases / physiology Lipopolysaccharides / pharmacology MAP Kinase Signaling System / drug effects Mice Mice, Inbred C57BL Mice, Knockout Microglia / metabolism* NF-KappaB Inhibitor alpha NF-kappa B / metabolism Poly I-C / pharmacology RNA, Messenger / biosynthesis RNA, Messenger / genetics Receptors, G-Protein-Coupled / antagonists & inhibitors Receptors, G-Protein-Coupled / deficiency Receptors, G-Protein-Coupled / physiology Second Messenger Systems / drug effects Second Messenger Systems / physiology*
IF 4.066
Times Cited 25
Human and Animal Cells MG6(RCB2403)