Selective inhibition of neutrophil function by a peptide derived from lipocortin 1 N-terminus.
A multi-faceted approach was used to investigate the effect of an anti-inflammatory peptide derived from human lipocortin 1 N-terminus region (amino acid 2-26; termed human Ac2-26) on human neutrophil activation in vitro. When incubated with purified human neutrophils. human Ac2-26 produced a concentration-dependent inhibition of elastase release stimulated by formyl-Met-Leu-Phe (fMLP), platelet-activating factor, or leukotriene B4, with an approximate EC50 of 33 microM (100 micrograms/ml). At this concentration, human Ac2-26 also inhibited (77%) the release of [3H]-arachidonic acid from neutrophils stimulated with fMLP. The peptide, however, did not inhibit the up-regulation of the beta 2-integrin CD11b and the concomitant shedding of L-selectin from neutrophil plasma membrane induced by fMLP. In adhesion experiments, human Ac2-26 inhibited neutrophil adhesion to endothelial monolayers when this was stimulated with fMLP, but not when this followed endothelial cell activation with histamine or platelet-activating factor. Again, the effect of the peptide was concentration-dependent, and an approximate EC50 of 33 microM was calculated. When a preparation of 125I-labeled human Ac2-26 was incubated with the neutrophils, the peptide was internalised in an energy-dependent fashion. All together, these observations lead us to propose a model in which this peptide derived from the N-terminus of human lipocortin 1 alters a common cellular mechanism producing a selective inhibition of neutrophil activation.
Perretti
M
M
Department of Biochemical Pharmacology, William Harvey Research Institute, Medical College of St. Bartholomew's Hospital, London, U.K.
Wheller
S K
SK
Choudhury
Q
Q
Croxtall
J D
JD
Flower
R J
RJ
D000595:Amino Acid Sequence; D017305:Annexin A1 / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D006801:Humans; D019041:L-Selectin / Q000378:metabolism; D008969:Molecular Sequence Data; D009240:N-Formylmethionine Leucyl-Phenylalanine; D018375:Neutrophil Activation / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects* / Q000502:physiology; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010455:Peptides
D017305:Annexin A1; D000894:Anti-Inflammatory Agents, Non-Steroidal; D010446:Peptide Fragments; D010455:Peptides; C096153:annexin A1 peptide (2-26); D019041:L-Selectin; D009240:N-Formylmethionine Leucyl-Phenylalanine