INHIBITION BY FK506 OF FORMYL PEPTIDE-INDUCED NEUTROPHIL ACTIVATION AND ASSOCIATED PROTEIN-SYNTHESIS

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.