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.
Noman
Abu Shadat M
AS
Department of Microbiology and Immunology, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.
Koide
Naoki
N
Hassan
Ferdaus
F
I-E-Khuda
Imtiaz
I
Dagvadorj
Jargalsaikhan
J
Tumurkhuu
Gantsetseg
G
Islam
Shamima
S
Naiki
Yoshikazu
Y
Yoshida
Tomoaki
T
Yokochi
Takashi
T
D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D015536:Down-Regulation / Q000276:immunology; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D007976:Leupeptins / Q000494:pharmacology; D018950:Lipopolysaccharide Receptors / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D053594:Myeloid Differentiation Factor 88 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000276:immunology; D046988:Proteasome Endopeptidase Complex / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D061988:Proteasome Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000276:immunology / Q000378:metabolism; D013792:Thalidomide / Q000494:pharmacology*; D051195:Toll-Like Receptor 2 / Q000276:immunology / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism
D015853:Cysteine Proteinase Inhibitors; D020672:I-kappa B Proteins; D007166:Immunosuppressive Agents; D007976:Leupeptins; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D061988:Proteasome Inhibitors; D048029:TNF Receptor-Associated Factor 6; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D013792:Thalidomide; D053592:Interleukin-1 Receptor-Associated Kinases; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde