Inhibition by FK506 of formyl peptide-induced neutrophil activation and associated protein synthesis

Research output: Contribution to journalArticle

Authors

  • D Burnett
  • D H Adams
  • Q Liu
  • R A Grant
  • R A Stockley
  • J M Lord

Abstract

The macrolide FK506 inhibited, by up to 50%, neutrophil migration and the production of the superoxide radical in response to the formyl peptide, 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 cellular proteins, despite a rise in intracellular Ca2+. Neutrophils treated with FK506 demonstrated a small (average 23%) though significant decrease in formyl-peptide receptor numbers but receptor binding affinity was unaffected. The effects of FK506 on neutrophil activation appear to be analogous to those in T-lymphocytes. The incomplete inhibition, by FK506, of neutrophil responses suggests further that activation by FMLP is mediated via distinct multiple signalling pathways, including protein kinase activation and protein synthesis. The inability of FK506 to reduce FMLP-induced rises in cellular Ca2+ or PMA-induced activation of neutrophils suggests that its action is distal to Ca2+ mobilization and distinct from pathways relying on PKC activation. Thus the immunosuppressive effects of FK506 in vivo might be mediated through the inhibition of inflammatory cells other than lymphocytes and the drug therefore has therapeutic potential in a variety of inflammatory conditions. The drug also has potential in vitro for the characterization of signalling pathways from the plasma membrane to the nucleus.

Details

Original languageEnglish
Pages (from-to)1081-8
Number of pages8
JournalBiochemical Pharmacology
Volume48
Issue number6
Publication statusPublished - 15 Sep 1994

Keywords

  • Calcium, Humans, N-Formylmethionine Leucyl-Phenylalanine, Neutrophil Activation, Protein Biosynthesis, Receptors, Formyl Peptide, Receptors, Immunologic, Receptors, Peptide, Superoxides, Tacrolimus, Tetradecanoylphorbol Acetate