TNF alpha signaling beholds thalidomide saga: a review of mechanistic role of TNF-alpha signaling under thalidomide.

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Majumder S, Sreedhara SR, Banerjee S, Chatterjee S

TNF alpha signaling beholds thalidomide saga: a review of mechanistic role of TNF-alpha signaling under thalidomide.

Curr Top Med Chem. 2012;12(13):1456-67. doi: 10.2174/156802612801784443.

PubMed ID
22650377 [ View in PubMed
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Abstract

Tumor necrosis factor alpha (TNF-alpha) is a pleiotropic inflammatory cytokine. The cytokine possesses both growth stimulating properties and growth inhibitory processes, and it appears to have self regulatory properties as well. Agents like etanercept and infliximab showed beneficial effects against rheumatoid arthritis by modulationg TNF-alpha proteins, however, these agents are largely unable to penetrate the blood-brain barrier, which severely limits their use in different conditions. Thalidomide, an inhibitor of TNF-alpha protein synthesis is readily capable of crossing the blood-brain barrier and thus thalidomide and its analogs are excellent candidates for use in determining the potential value of anti-TNF-alpha therapies in a variety of diseases. Thalidomide blocks TNF-alpha expression by different possible mechanisms. Down regulation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), an essential transcription factor for TNF and other cytokines under thalidomide treatment leads to reduction in the TNF-alpha expression. Additionally, myeloid differentiation factor 88 (MyD88), an adapter protein regulates the expression of TNF under thalidomide treatment. Thalidomide treatment also leads to destruction of TNF-alpha mRNA thus, reducing the total expression of TNF-alpha protein. Thalidomide also targets reactive oxygen species (ROS) and alpha(1)-acid glycoprotein (AGP) to regulate TNF-alpha. In the present review, we discuss different possible mechanism that regulates TNF-alpha under thalidomide treatment. Additionally, we suggest novel strategies for the future targeting combination therapies of thalidomide and its analogs with different other anti-inflammatory drug to curb TNF-alpha associated diseases.

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