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Flavopiridol inhibits lipopolysaccharide‐induced TNF‐α production through inactivation of nuclear factor‐κB and mitogen‐activated protein kinases in the MyD88‐dependent pathway
Author(s) -
Haque Abedul,
Koide Naoki,
IftakharEKhuda Imtiaz,
Noman Abu Shadat Mohammod,
Odkhuu Erdenezaya,
Badamtseren Battuvshin,
Naiki Yoshikazu,
Komatsu Takayuki,
Yoshida Tomoaki,
Yokochi Takashi
Publication year - 2011
Publication title -
microbiology and immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.664
H-Index - 70
eISSN - 1348-0421
pISSN - 0385-5600
DOI - 10.1111/j.1348-0421.2010.00304.x
Subject(s) - kinase , ask1 , biology , cancer research , protein kinase a , microbiology and biotechnology , p38 mitogen activated protein kinases , map kinase kinase kinase , mitogen activated protein kinase kinase , mitogen activated protein kinase , signal transduction
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.