D. Burnett et al., INHIBITION BY FK506 OF FORMYL PEPTIDE-INDUCED NEUTROPHIL ACTIVATION AND ASSOCIATED PROTEIN-SYNTHESIS, Biochemical pharmacology, 48(6), 1994, pp. 1081-1088
The macrolide FK506 inhibited, by up to 50%, neutrophil migration and
the production of the superoxide radical in response to the formyl pep
tide, formyl-methionyl-leucyl-phenylalanine (FMLP). The production of
the superoxide radical in response to phorbol 12-myristate 13-acetate
(PMA) was unaffected by FK506. The inhibition of neutrophil functions
was accompanied by a partial reversal of FMLP-induced synthesis of cel
lular proteins, despite a rise in intracellular Ca2+. Neutrophils trea
ted with FK506 demonstrated a small (average 23%) though significant d
ecrease in formyl-peptide receptor numbers but receptor binding affini
ty was unaffected. The effects of FK506 on neutrophil activation appea
r to be analogous to those in T-lymphocytes. The incomplete inhibition
, by FK506, of neutrophil responses suggests further that activation b
y FMLP is mediated via distinct multiple signalling pathways, includin
g protein kinase activation and protein synthesis. The inability of FK
506 to reduce FMLP-induced rises in cellular Ca2+ or PMA-induced activ
ation of neutrophils suggests that its action is distal to Ca2+ mobili
zation and distinct from pathways relying on PKC activation. Thus the
immunosuppressive effects of FK506 in vivo might be mediated through t
he inhibition of inflammatory cells other than lymphocytes and the dru
g therefore has therapeutic potential in a variety of inflammatory con
ditions. The drug also has potential in vitro for the characterization
of signalling pathways from the plasma membrane to the nucleus.