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

Abstract

The effect of thalidomide on lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-a production was studied by using RAW 264.7 murine macrophage-like cells. Thalidomide significantly inhibited LPS-induced TNF-a production. Thalidomide prevented the activation of nuclear factor (NF)-kB by down-regulating phosphorylation of inhibitory kB factor (IkB), and IkB kinase (IKK)-a and IKK-b 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-a 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-a production. The putative mechanism of thalidomide-induced MyD88 down-regulation is discussed.

Thalidomide treatment modulates macrophage pro-inflammatory function and cytokine levels in Klebsiella pneumoniae B5055 induced pneumonia in BALB/c mice

“…These results show deleterious effect of thalidomide on proinflammatory cytokine production and accentuation of IL-10 production. Recently, Noman et al have shown that thalidomide inhibits TNF-α production from RAW 264.7 murine macrophages-like cells, when they are stimulated with lipopolysaccharide (LPS) by inhibiting the NF-κB pathway [33]. They found that thalidomide treatment decreased the expression of myeloid differentiation factor 88 (MyD88) protein and mRNA in the macrophages, involved in NF-κB mediated down signaling leading to exaggerated inflammatory immune response in response to infectious or inflammatory agent.…”

Anti-inflammatory aminoacetylenic isoindoline-1,3-dione derivatives modulate cytokines production from different spleen cell populations

“…The suppression activity of all ZM compounds against LPS-induced TNF-α production is mainly attributed to the isoindoline1,3-dione moiety in the ZM compounds. It has been shown that phthalimide (isoindoline1,3-dione) and thalidomide analogues do inhibit synthesis of TNF-α from LPS-activated macrophages through impairing the intracellular LPS signaling such as NF-kB activation, MyD88 expression and p38 phosphorylation [28][29][30][31]. Furthermore, since oral administration 20 mg/kg of ZM compounds showed antiinflammatory in carrageenan-induced rat paw edema within hours post administration [9] and modulated LPS-induced cytokine in mice spleen, these ZM compounds are readily bioavailable in blood and suggest proper pharmacokinetic properties for anti-inflammatory drugs.…”

A glycoprotein from Porphyra yezoensis produces anti-inflammatory effects in liposaccharide-stimulated macrophages via the TLR4 signaling pathway

“…Activation of the MyD88-dependent pathway involves the sequential recruitment of the adaptor molecule MyD88, IRAK family proteins and TRAF6 (38,39). TRAF6 subsequently triggers the activation of MAP kinases and, as a result of TAK-1-mediated IKK activation, NF-κB (40).…”