Suppressive effects of cyclosporin A and FK-506 on superoxide generation in human polymorphonuclear leukocytes primed by tumor necrosis factor alpha

Most previous studies have found no effects of cyclosporin A and FK-506 on active oxygen generation in human polymorphonuclear leukocytes. Recently va rious differences in biologic properties have been reported between unprime d peripheral blood human polymorphonuclear leukocytes and tissue or primed human polymorphonuclear leukocytes. In this study, we investigated the effe cts of cyclosporin A and FK-506 on superoxide (O-2(-)) generation induced b y the chemotactic peptide N-formyl-Lmethionyl-L-leucyl-Lphenylalanine in hu man peripheral blood polymorphonuclear leukocytes primed or unprimed with t umor necrosis factor alpha. Neither cyclosporin A nor FK-506 suppressed N-f ormyl-L-methionyl-L-leucyl-Lphenylalanine-induced O-2(-) generation in unpr imed human polymorphonuclear leukocytes at concentrations between 0.1 nM an d 10 muM, as in previous studies. Only at 1 muM of cyclosporin A and 100 nM of FK-506 were marginal suppressive effects observed. On the other hand, c yclosporin A and FK-506 both suppressed N-formyl-L-methionyl-L-leucyl-L-phe nylalanine-induced O-2(-) generation in tumor-necrosis-factor-alpha -primed human polymorphonuclear leukocytes, strongly and dose dependently, at conc entrations between 1 nM and 1 muM. Neither cyclosporin A nor FK-506 influen ced tyrosyl phosphorylation of 115 kDa protein, which is inducible during t he priming process, suggesting that neither cyclosporin A nor FK-506 influe nced the tumor-necrosis-factor-alpha -induced priming process itself, and i nstead modified the biologic response of primed human polymorphonuclear leu kocytes.