A novel Mutein of TNFα Containing the Arg-Gly-Asp Sequence Shows Reduced Toxicity in Intestine

[摘要] The effects of human tumour necrosis factor-α (TNFα), or itsmutein (F4168) having the cell adhesive Arg-Gly-Asp sequence at theN-terminus, on intestinal injury, were examined. Histopathologicalexamination revealed that an intravenous injection of TNFαresulted in marked haemorrhage or oedema in the caecum of rats,whereas F4168 showed no such effects even at the same therapeuticdose. Moreover, the number of neutrophils that adhered toendothelial cells or infiltrated the mucosal tissue was much higherafter TNFα injection compared with F4168in vivo.The enhanced adhesion of neutrophils on to human umbilical veinendothelial cells also occurred when the latter were pre-stimulatedwith TNFα but not with F4168in vitro. Theexpression of the cell adhesion molecules including endothelialleukocyte adhesion molecule-1 or intercellular adhesion molecule-1on F4168- stimulated human umbilical vein endothelial ceils wassignificantly lower than that stimulated with TNFα. Theseresults suggest that the Arg-Gly-Asp sequence introduced into theTNFα molecule abrogates the side effect of this cytokine suchas tissue injury or shock, and that F4168 could be useful forsystemic therapy.

[学科分类] 生理学与病理学