title: Activation of adenosine A3 receptor suppresses lipopolysaccharide-induced TNF-alpha production through inhibition of PI 3-kinase/Akt and NF-kappaB activation in murine BV2 microglial cells.
abstract: Adenosine is an endogenous nucleoside that regulates many processes, including inflammatory responses, through activation of its receptors. Adenosine receptors have been reported to be expressed in microglia, which are major immune cells of brain, yet little is known about the role of adenosine receptors in microglial cytokine production. Thus, we investigated the effect of adenosine and adenosine A3 receptor ligands on LPS-induced tumor necrosis factor (TNF-alpha) production and its molecular mechanism in mouse BV2 microglial cells. Adenosine and Cl-IB-MECA, a specific adenosine A3 receptor agonist, suppressed LPS-induced TNF-alpha protein and mRNA levels. Moreover, MRS1523, a selective A3 receptor antagonist, blocked suppressive effects of both adenosine and Cl-IB-MECA on TNF-alpha. We further examined the effect of adenosine on signaling molecules, such as PI 3-kinase, Akt, p38, ERK1/2, and NF-kappaB, which are involved in the regulation of inflammatory responses. Adenosine inhibited LPS-induced phosphatidylinositol (PI) 3-kinase activation and Akt phosphorylation, whereas it had no effect on the phosphorylation of p38 and ERK1/2. We also found that adenosine as well as Cl-IB-MECA inhibited LPS-induced NF-kappaB DNA binding and luciferase reporter activity. Taken together, these results suggest that adenosine A3 receptor activation suppresses TNF-alpha production by inhibiting PI 3-kinase/Akt and NF-kappaB activation in LPS-treated BV2 microglial cells.
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, 1 Hoegi-dong, Seoul 130-701, Korea.
authors.forename: Jung Yeon
authors.initials: JY
authors.lastname: Lee
authors.forename: Bong Sook
authors.initials: BS
authors.lastname: Jhun
authors.forename: Young Taek
authors.initials: YT
authors.lastname: Oh
authors.forename: Ju Hie
authors.initials: JH
authors.lastname: Lee
authors.forename: Wonchae
authors.initials: W
authors.lastname: Choe
authors.forename: Hyung Hwan
authors.initials: HH
authors.lastname: Baik
authors.forename: Joohun
authors.initials: J
authors.lastname: Ha
authors.forename: Kyung-Sik
authors.initials: KS
authors.lastname: Yoon
authors.forename: Sung Soo
authors.initials: SS
authors.lastname: Kim
authors.forename: Insug
authors.initials: I
authors.lastname: Kang
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D058909:Adenosine A3 Receptor Agonists; D058918:Adenosine A3 Receptor Antagonists; D000818:Animals; D002460:Cell Line; D004660:Encephalitis / Q000378:metabolism / Q000503:physiopathology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005911:Gliosis / Q000378:metabolism / Q000503:physiopathology; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D043684:Receptor, Adenosine A3 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: C419146:2,3-diethyl-4,5-dipropyl-6-phenylpyridine-3-thiocarboxylate-5-carboxylate; D058909:Adenosine A3 Receptor Agonists; D058918:Adenosine A3 Receptor Antagonists; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011725:Pyridines; D012333:RNA, Messenger; D043684:Receptor, Adenosine A3; D014409:Tumor Necrosis Factor-alpha; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D000241:Adenosine; C090034:2-chloro-N(6)-(3-iodobenzyl)adenosine-5'-N-methyluronamide