title: Melatonin inhibits visfatin-induced inducible nitric oxide synthase expression and nitric oxide production in macrophages.
abstract: Aberrant expression of inducible nitric oxide synthase (iNOS) in macrophages, which has been reported to be suppressed by melatonin, has an important contribution in the development of pathological inflammation. Visfatin, an adipokine, regulates the expression of various inflammatory factors, leading to inflammation; however, the influence of visfatin on iNOS-driven processes in macrophages is unclear. Here, we report the assessment of the role of visfatin in the regulation of iNOS gene expression in macrophages. Our data show that the levels of iNOS protein in peritoneal macrophages as well as nitric oxide (NO) in blood plasma were significantly lower after lipopolysaccharide treatment in visfatin(+/-) mice than those in the WT mice. In addition, visfatin increases iNOS mRNA and protein levels in RAW 264.7 cells, along with increasing production of NO. The enhancement of iNOS expression was prevented by treating the cells with inhibitors of the Janus kinase 2/signal transducers and activators of transcription 3 (JAK2/STAT3), nuclear factor (NF)-κB, extracellular signal-regulated kinase 1/2, and c-Jun N-terminal kinase pathways. Our results also show that visfatin-induced iNOS expression and NO production were significantly inhibited by melatonin, an effect that was closely associated with a reduction in phosphorylated JAK2/STAT3 levels and with the inhibition of p65 translocation into nucleus. In conclusion, our data show, for the first time, that melatonin suppresses visfatin-induced iNOS upregulation in macrophages by inhibiting the STAT3 and NF-κB pathways. Moreover, our data suggest that melatonin could be therapeutically useful for attenuating the development of visfatin-iNOS axis-associated diseases.
authors.affiliation: Department of Dental Pharmacology, School of Dentistry, Yangsan Campus of Pusan National University, Yangsan, South Korea.
authors.forename: Young-Soon
authors.initials: YS
authors.lastname: Kang
authors.forename: Yong-Gyu
authors.initials: YG
authors.lastname: Kang
authors.forename: Hyun-Joo
authors.initials: HJ
authors.lastname: Park
authors.forename: Hee-Jun
authors.initials: HJ
authors.lastname: Wee
authors.forename: Hye-Ock
authors.initials: HO
authors.lastname: Jang
authors.forename: Moon-Kyoung
authors.initials: MK
authors.lastname: Bae
authors.forename: Soo-Kyung
authors.initials: SK
authors.lastname: Bae
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002460:Cell Line; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects* / Q000235:genetics; D053614:Janus Kinase 2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053616:Janus Kinase 3 / Q000235:genetics / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000201:enzymology*; D008550:Melatonin / Q000494:pharmacology*; D051379:Mice; D008817:Mice, Mutant Strains; D048055:Mitogen-Activated Protein Kinase 8 / Q000235:genetics / Q000378:metabolism; D048056:Mitogen-Activated Protein Kinase 9 / Q000235:genetics / Q000378:metabolism; D054409:Nicotinamide Phosphoribosyltransferase / Q000235:genetics / Q000378:metabolism*; D009569:Nitric Oxide / Q000096:biosynthesis* / Q000235:genetics; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D000975:Antioxidants; D016207:Cytokines; D012333:RNA, Messenger; C498144:Rela protein, mouse; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D051996:Transcription Factor RelA; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D054409:Nicotinamide Phosphoribosyltransferase; C495867:nicotinamide phosphoribosyltransferase, mouse; D048056:Mitogen-Activated Protein Kinase 9; C507926:Jak2 protein, mouse; C507935:Jak3 protein, mouse; D053614:Janus Kinase 2; D053616:Janus Kinase 3; D048055:Mitogen-Activated Protein Kinase 8; D008550:Melatonin
keywords: NF-κB; STAT3; inducible nitric oxide synthase; macrophages; melatonin; visfatin