title: 5-Aminoimidazole-4-carboxamide riboside suppresses lipopolysaccharide-induced TNF-alpha production through inhibition of phosphatidylinositol 3-kinase/Akt activation in RAW 264.7 murine macrophages.
abstract: 5-Aminoimidazole-4-carboxamide riboside (AICAR) is an adenosine analog and a widely used activator of AMP-activated protein kinase (AMPK). We examined the effect of AICAR on LPS-induced TNF-alpha production in RAW 264.7 and peritoneal macrophages and its molecular mechanism in RAW 264.7 macrophages. Treatment with AICAR inhibited LPS-induced increases in TNF-alpha mRNA and protein levels in these cells. AICAR or LPS did not alter the AMPK activity as well as the phosphorylations of AMPK alpha (Thr172) and ACC (Ser79). Moreover, an adenosine kinase inhibitor 5'-iodotubercidin enhanced the suppressive effect of AICAR on TNF-alpha levels. These results suggest that the effect of AICAR on TNF-alpha suppression in RAW 264.7 cells is independent of AMPK activation. In addition, an adenosine receptor antagonist 8-SPT had no effect on AICAR-induced suppression of TNF-alpha levels. Finally, we observed that AICAR inhibited LPS-induced activation of PI 3-kinase and Akt, whereas it had no effect on the activation of p38 and ERK1/2. Taken together, these results suggest that the anti-inflammatory action of AICAR in RAW 264.7 macrophages is independent of AMPK activation and is associated with inhibition of LPS-induced activation of PI 3-kinase/Akt pathway.
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea.
authors.forename: Bong Sook
authors.initials: BS
authors.lastname: Jhun
authors.forename: Quanri
authors.initials: Q
authors.lastname: Jin
authors.forename: Young Taek
authors.initials: YT
authors.lastname: Oh
authors.forename: Sung Soo
authors.initials: SS
authors.lastname: Kim
authors.forename: Yoon
authors.initials: Y
authors.lastname: Kong
authors.forename: Yong Ho
authors.initials: YH
authors.lastname: Cho
authors.forename: Joohun
authors.initials: J
authors.lastname: Ha
authors.forename: Hyung Hwan
authors.initials: HH
authors.lastname: Baik
authors.forename: Insug
authors.initials: I
authors.lastname: Kang
mesh_terms: D055372:AMP-Activated Protein Kinases; D000241:Adenosine / Q000037:antagonists & inhibitors; D000248:Adenosine Kinase / Q000037:antagonists & inhibitors; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009097:Multienzyme Complexes / Q000378:metabolism; D033703:Nucleoside Transport Proteins / Q000037:antagonists & inhibitors; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D058915:Purinergic P1 Receptor Antagonists; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D051381:Rats; D012265:Ribonucleotides / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
chemical_list: D055372:AMP-Activated Protein Kinases; D000241:Adenosine; D000248:Adenosine Kinase; D000620:Aminoimidazole Carboxamide; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D020928:Mitogen-Activated Protein Kinases; D009097:Multienzyme Complexes; D033703:Nucleoside Transport Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D058915:Purinergic P1 Receptor Antagonists; D012333:RNA, Messenger; D012265:Ribonucleotides; D014409:Tumor Necrosis Factor-alpha; C494920:Akt1 protein, rat; C031143:AICA ribonucleotide