The anti-inflammatory peptides, antiflammins, regulate the expression of adhesion molecules on human leukocytes and prevent neutrophil adhesion to endothelial cells.
Antiflammin-1 and antiflammin-2 are nonapeptides corresponding to the region of highest similarity between glucocorticoid-inducible proteins lipocortin-1 and uteroglobin. We have studied whether antiflammins could affect expression of adhesion molecules on human leukocytes and coronary artery endothelial cells (HCAEC) and binding of neutrophils (PMNs) to HCAEC. Although neither antiflammin-1 nor antiflammin-2 affected expression of adhesion molecules on resting PMNs, monocytes, and lymphocytes in whole blood, they attenuated changes in L-selectin and CD11/CD18 expression evoked by platelet-activating factor or interleukin-8 with IC(50) values of 4-20 micromol/l. The maximum inhibition was similar to those seen with human recombinant lipocortin-1 (100 microgram/ml). Unlike dexamethasone (100 nmol/l), the antiflammins had little effect on LPS-stimulated expression of E-selectin and ICAM-1 on HCAEC. Consistently, culture of HCAEC with dexamethasone, but not with antiflammins, decreased PMN binding to endothelial cells. Preincubation of PMNs with antiflammins markedly decreased their adhesion to LPS-activated HCAEC. Inhibition of adhesion was additive with function blocking anti-E-selectin and anti-L-selectin antibodies, but was not additive with anti-CD18 antibody. These results show that antiflammins inhibit PMN adhesion to HCAEC by attenuating activation-induced up-regulation of CD11/CD18 expression on leukocytes, and suggest that antiflammins may represent a novel therapeutic approach in blocking leukocyte trafficking in host defense and inflammation.
Zouki
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C
Research Center, Maisonneuve-Rosemont Hospital, Department of Medicine, University of Montréal, Montréal, Québec, Canada H1T 2M4.
Ouellet
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S
Filep
J G
JG
D000328:Adult; D017305:Annexin A1 / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D018821:CD18 Antigens / Q000235:genetics; D002448:Cell Adhesion / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D003331:Coronary Vessels; D019040:E-Selectin / Q000235:genetics*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics*; D007700:Kinetics; D007962:Leukocytes / Q000187:drug effects / Q000502:physiology*; D008214:Lymphocytes / Q000187:drug effects / Q000502:physiology; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000502:physiology; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D009842:Oligopeptides / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology*; D010972:Platelet Activating Factor / Q000494:pharmacology; D014598:Uteroglobin / Q000494:pharmacology*
D017305:Annexin A1; D000894:Anti-Inflammatory Agents, Non-Steroidal; D018821:CD18 Antigens; D019040:E-Selectin; D009842:Oligopeptides; D010446:Peptide Fragments; D010972:Platelet Activating Factor; C064645:antiflammin P1; C064647:antiflammin P2; D018799:Intercellular Adhesion Molecule-1; D014598:Uteroglobin