title: Flavopiridol inhibits lipopolysaccharide-induced TNF-α production through inactivation of nuclear factor-κB and mitogen-activated protein kinases in the MyD88-dependent pathway.
abstract: Flavopiridol is a cyclin-dependent kinase inhibitor and inhibits the growth of various cancer cells. The effect of flavopiridol on lipopolysaccharide (LPS)-induced proinflammatory mediator production was examined in RAW 264.7 macrophage-like cells. Flavopiridol significantly reduced the production of tumor necrosis factor-α and, to a lesser extent, nitric oxide in LPS-stimulated cells. Flavopiridol inhibited the activation of nuclear factor-κB and IκB kinase in response to LPS. Flavopiridol also inhibited the activation of a series of mitogen-activated protein kinases, such as p38, stress-activated protein kinase/c-Jun N-terminal kinase and extracellular signal-regulated kinase 1/2 in response to LPS. However, flavopiridol did not alter the expression of tumor necrosis factor receptor-associated factor 6, myeloid differentiation factor 88 (MyD88) or CD14/toll-like receptor (TLR) 4. Flavopiridol inhibited nitric oxide production induced by a MyD88-dependent TLR2 ligand, but not a MyD88-independent TLR3 ligand. Further, flavopiridol did not alter the phosphorylation of interferon regulatory factor 3 in the MyD88-independent pathway. Therefore, it was suggested that flavopiridol exclusively inhibited the activation of nuclear factor-κB and mitogen-activated protein kinases in the MyD88-dependent pathway. Flavopiridol might be useful for the prevention of LPS-induced inflammatory response.
authors.affiliation: Department of Microbiology and Immunology, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.
authors.forename: Abedul
authors.initials: A
authors.lastname: Haque
authors.forename: Naoki
authors.initials: N
authors.lastname: Koide
authors.forename: Imtiaz
authors.initials: I
authors.lastname: Iftakhar-E-Khuda
authors.forename: Abu Shadat Mohammod
authors.initials: AS
authors.lastname: Noman
authors.forename: Erdenezaya
authors.initials: E
authors.lastname: Odkhuu
authors.forename: Battuvshin
authors.initials: B
authors.lastname: Badamtseren
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Naiki
authors.forename: Takayuki
authors.initials: T
authors.lastname: Komatsu
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Yoshida
authors.forename: Takashi
authors.initials: T
authors.lastname: Yokochi
mesh_terms: D000818:Animals; D002460:Cell Line; D005419:Flavonoids / Q000494:pharmacology*; D019848:Gene Expression Regulation, Archaeal / Q000187:drug effects*; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D009569:Nitric Oxide / Q000096:biosynthesis; D010766:Phosphorylation / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
chemical_list: D005419:Flavonoids; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D048029:TNF Receptor-Associated Factor 6; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; C077990:alvocidib; D020928:Mitogen-Activated Protein Kinases