|Author||Noman AS, Koide N, Hassan F, I-E-Khuda I, Dagvadorj J, Tumurkhuu G, Islam S, Naiki Y, Yoshida T, Yokochi T.|
|Title||Thalidomide inhibits lipopolysaccharide-induced tumor necrosis factor-alpha production via down-regulation of MyD88 expression.|
The effect of thalidomide on lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-alpha production was studied by using RAW 264.7 murine macrophage-like cells. Thalidomide significantly inhibited LPS-induced TNF-alpha production. Thalidomide prevented the activation of nuclear factor (NF)-KB by down-regulating phosphorylation of inhibitory KB factor (IKB), and IKB kinase (IKK)-alpha and IKK-beta Moreover, thalidomide inhibited LPS-induced phosphorylation of AKT, p38 and stress-activated protein kinase (SAPK)/JNK. The expression of myeloid differentiation factor 88 (MyD88) protein and mRNA was markedly reduced in thalidomide-treated RAW 264.7 cells but there was no significant alteration in the expression of interleukin-1 receptor-associated kinase (IRAK) 1 and TNF receptor-associated factor (TRAF) 6 in the cells. Thalidomide did not affect the cell surface expression of Toll-like receptor (TLR) 4 and CD14, suggesting the impairment of intracellular LPS signalling in thalidomide-treated RAW 264.7 cells. Thalidomide significantly inhibited the TNF-alpha production in response to palmitoyl-Cys(RS)-2,3-di(palmitoyloxy) propyl)-Ala-Gly-OH (Pam(3)Cys) as a MyD88-dependent TLR2 ligand. Therefore, it is suggested that thalidomide might impair LPS signalling via down-regulation of MyD88 protein and mRNA and inhibit LPS-induced TNF-alpha production. The putative mechanism of thalidomide-induced MyD88 down-regulation is discussed.
|MeSH||Animals Cell Line Cells, Cultured Cysteine Proteinase Inhibitors / pharmacology Down-Regulation / immunology I-kappa B Proteins / antagonists & inhibitors I-kappa B Proteins / immunology I-kappa B Proteins / metabolism Immunosuppressive Agents / pharmacology* Interleukin-1 Receptor-Associated Kinases / antagonists & inhibitors Interleukin-1 Receptor-Associated Kinases / immunology Interleukin-1 Receptor-Associated Kinases / metabolism JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors JNK Mitogen-Activated Protein Kinases / immunology JNK Mitogen-Activated Protein Kinases / metabolism Leupeptins / pharmacology Lipopolysaccharide Receptors / drug effects Lipopolysaccharide Receptors / immunology Lipopolysaccharide Receptors / metabolism Lipopolysaccharides / immunology Macrophages / drug effects Macrophages / immunology Mice Mice, Inbred BALB C Myeloid Differentiation Factor 88 / antagonists & inhibitors* Myeloid Differentiation Factor 88 / metabolism NF-kappa B / antagonists & inhibitors NF-kappa B / immunology NF-kappa B / metabolism Phosphorylation / drug effects Phosphorylation / immunology Proteasome Endopeptidase Complex / immunology Proteasome Endopeptidase Complex / metabolism Proteasome Endopeptidase Complex / pharmacology Proteasome Inhibitors Proto-Oncogene Proteins c-akt / antagonists & inhibitors Proto-Oncogene Proteins c-akt / immunology Proto-Oncogene Proteins c-akt / metabolism TNF Receptor-Associated Factor 6 / immunology TNF Receptor-Associated Factor 6 / metabolism Thalidomide / pharmacology* Toll-Like Receptor 2 / immunology Toll-Like Receptor 2 / metabolism Toll-Like Receptor 4 / antagonists & inhibitors Toll-Like Receptor 4 / immunology Toll-Like Receptor 4 / metabolism Tumor Necrosis Factor-alpha / antagonists & inhibitors* Tumor Necrosis Factor-alpha / biosynthesis p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors p38 Mitogen-Activated Protein Kinases / immunology p38 Mitogen-Activated Protein Kinases / metabolism|
|Human and Animal Cells||RAW 264 (RCB0535)|