Selective inhibition of neutrophil function by a peptide derived from lipocortin 1 N-terminus

• Published in: Biochemical pharmacology Vol. 50; no. 7; pp. 1037 - 1042
• Main Authors: Perretti, Mauro, Wheller, Samantha K., Choudhury, Qamrul, Croxtall, Jamie D., Flower, Roderick J.
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 28.09.1995; Elsevier Science
• Subjects: adhesion molecules; Amino Acid Sequence; Annexin A1 - chemistry; Annexin A1 - metabolism; Annexin A1 - pharmacology; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; arachidonic acid; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; cell adhesion; Cell Adhesion - drug effects; elastase; F-actin; Humans; inflammation; L-Selectin - metabolism; Medical sciences; Molecular Sequence Data; N-Formylmethionine Leucyl-Phenylalanine; Neutrophil Activation - drug effects; Neutrophils - drug effects; Neutrophils - physiology; Peptide Fragments - chemistry; Peptide Fragments - metabolism; Peptide Fragments - pharmacology; Peptides; Pharmacology. Drug treatments; arachidonic acid; fMLPL; AA; fMLP; DNP; FACS; elastase; PMN; NBD; MFI; DMEM; F-actin; PAF; adhesion molecules; inflammation; 2DG; cell adhesion; FCS; LTB 4; LC1; HBSS; PLA 2; Human; Cell function; Peptides; Antiinflammatory agent; Lipocortin; Neutrophil; Mechanism of action; N terminal peptide; In vitro; Biological activity
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/0006-2952(95)00238-U

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 B 4, with an approximate EC 50 of 33 μM (100 μg/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 β 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 EC 50 of 33 μM 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.