A Synthetic Peptide Derived from A1 Module in CRD4 of Human TNF Receptor-1 Inhibits Binding and Proinflammatory Effect of Human TNF-α

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Abstract

Tumour necrosis factor α (TNF-α) is a proinflammatory cytokine, which has been shown to be a causative factor in rheumatoid arthritis, inflammatory bowel disease and septic shock. Proinflammatory effect of TNF-α is activated mainly through human TNF receptor-1 (TNF-R1). However, the role of the fourth cystein-rich domain (CRD4) of TNF-R1 extracellular portion in the interaction of TNF-α with TNF-R1 is still unclear. In the present study, binding activity of TNF-α to TNF-R1 and protein levels of IκB-α and nuclear transcription factor kappa B (NF-κB) p65 subunit in HeLa cells were measured using enzyme-linked immunosorbent assay (ELISA) and western-blot analysis. Pep 3 (LRENECVS) which was derived from the hydrophilic region of A1 module in CRD4 remarkably inhibited the binding of TNF-α to TNF-R1, and also reversed TNF-α-induced degradation of IκB-α and nuclear translocation of NF-κB p65 subunit in HeLa cells. Our results confirmed that the hydrophilic region of A1 module in CRD4 participated in the interaction of TNF-α with TNF-R1, and demonstrated the potential of small-molecule TNF-α extracellular inhibitors targeting at A1 module in CRD4 of TNF-R1 in suppressing proinflammatory effect of TNF-α.

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