Dissociation of TNF-alpha cytotoxic and proinflammatory activities by p55 receptor- and p75 receptor-selective TNF-alpha mutants.

摘要: Human tumour necrosis factor alpha (TNF-alpha) is a pleiotropic cytokine capable of killing mammalian cells in vitro and vivo, enhancing the proinflammatory activity leucocytes endothelium, latter effects limiting its usage as an antitumour agent humans. Using TNF-alpha mutants with selective capacity to bind TNF p55 receptor (TNFR55) or p75 (TNFR75) we show here that these two major activities can be dissociated. The TNFR55-selective (R32W, E146K R32W-S86T) which poorly TNFR75 displayed similar potency wild-type causing cytotoxicity human laryngeal carcinoma-derived cell line (HEp-2) cytostasis leukaemic (U937). However, exhibited lower than TNF. Specifically, TNF-alpha's priming neutrophils for superoxide production antibody-dependent cell-mediated cytotoxicity, platelet-activating synthesis adhesion endothelium were reduced by up 170-fold. Activation endothelial functions represented umbilical venular (HUVEC) adhesiveness neutrophils, E-selectin expression, neutrophil transmigration IL-8 secretion also 280-fold. On other hand, D143F, TNFR75-selective mutant tested either alone combination mutants, did not stimulate despite being able cause TNFR75-transfected PC60 cells.(ABSTRACT TRUNCATED AT 250 WORDS)