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Thalidomide inhibits lipopolysaccharide-induced tumor necrosis factor- production via down-regulation of MyD88 expression

Department of Microbiology and Immunology, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan

Naoki Koide

Department of Microbiology and Immunology, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan

Ferdaus Hassan

Department of Microbiology and Immunology, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan

Imtiaz I.-E-Khuda

Department of Microbiology and Immunology, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan

Jargalsaikhan Dagvadorj

Department of Microbiology and Immunology, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan

Gantsetseg Tumurkhuu

Department of Microbiology and Immunology, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan

Shamima Islam

Department of Microbiology and Immunology, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan

Yoshikazu Naiki

Department of Microbiology and Immunology, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan

Tomoaki Yoshida

Department of Microbiology and Immunology, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan

Takashi Yokochi

Department of Microbiology and Immunology, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan, yokochi{at}aichi-med-u.ac.jp

The effect of thalidomide on lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)- production was studied by using RAW 264.7 murine macrophage-like cells. Thalidomide significantly inhibited LPS-induced TNF- production. Thalidomide prevented the activation of nuclear factor (NF)-KB by down-regulating phosphorylation of inhibitory KB factor (IKB), and IKB kinase (IKK)- and IKK-β 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- production in response to palmitoyl-Cys(RS)-2,3-di(palmitoyloxy) propyl)-Ala-Gly-OH (Pam₃Cys) 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- production. The putative mechanism of thalidomide-induced MyD88 down-regulation is discussed.

Key Words: Thalidomide • LPS • TNF- • MyD88 • RAW 264.7 cells

Innate Immunity, Vol. 15, No. 1, 33-41 (2009)
DOI: 10.1177/1753425908099317


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