Metformin attenuates production of nitric oxide in response to lipopolysaccharide by inhibiting MyD88-independent pathway.
Metformin is reported to ameliorate inflammation in diabetic patients. The effect of metformin on lipopolysaccharide-induced nitric oxide production was studied by using RAW 264.7 macrophage-like cells. The action of metformin was analyzed by dividing lipopolysaccharide signaling into the MyD88-dependent and -independent pathways. Metformin significantly reduced the expression of an inducible type of nitric oxide synthase and inhibited lipopolysaccharide-induced nitric oxide production. On the other hand, metformin did not inhibit lipopolysaccharide-induced tumor necrosis factor-alpha production. The expression levels of interferon-beta protein and mRNA, which is a key molecule in MyD88-independent pathway, were significantly inhibited by metformin. Compound C, a specific AMP-activated protein kinase inhibitor, did not affect the inhibitory action of metformin. Metformin was suggested to inhibit lipopolysaccharide-induced nitric oxide production via inhibition of interferon-beta production in MyD88-independent pathway. Metformin might exhibit an anti- inflammatory action on diabetic complications as well as the antidiabetic action.
Kato
Y
Y
Department of Internal Medicine, Division of Endocrinology, Metabolism and Diabetes, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan. ykato4@aichi-med-u.ac.jp
Koide
N
N
Komatsu
T
T
Tumurkhuu
G
G
Dagvadorj
J
J
Kato
K
K
Yokochi
T
T
D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors; D000818:Animals; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis*; D011070:Poly I-C / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D016899:Interferon-beta; D008687:Metformin; D055372:AMP-Activated Protein Kinases; D011070:Poly I-C