The Journal of Experimental Medicine
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Published online 3 April 2000.
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© The Rockefeller University Press, 0022-1007/2000/4/1197/ $5.00
The Journal of Experimental Medicine, Volume 191, Number 7, April 3, 2000 1197-1208

Original Article

Activation of Lipoxin a4 Receptors by Aspirin-Triggered Lipoxins and Select Peptides Evokes Ligand-Specific Responses in Inflammation

Nan Chianga, Iolanda M. Fierroa, Karsten Gronerta, and Charles N. Serhana

a Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115
Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital, 75 Francis St., Boston, MA 02115.617-278-6957617-732-8822

cnserhan{at}zeus.bwh.harvard.edu

Lipoxin (LX) A4 and aspirin-triggered LX (ATL) are endogenous lipids that regulate leukocyte trafficking via specific LXA4 receptors (ALXRs) and mediate antiinflammation and resolution. ATL analogues dramatically inhibited human neutrophil (polymorphonuclear leukocyte [PMN]) responses evoked by a potent necrotactic peptide derived from mitochondria as well as a rogue synthetic chemotactic peptide. These bioactive lipid analogues and small peptides each selectively competed for specific 3H-LXA4 binding with recombinant human ALXR, and its N-glycosylation proved essential for peptide but not LXA4 recognition. Chimeric receptors constructed from receptors with opposing functions, namely ALXR and leukotriene B4 receptors (BLTs), revealed that the seventh transmembrane segment and adjacent regions of ALXR are essential for LXA4 recognition, and additional regions of ALXR are required for high affinity binding of the peptide ligands. Together, these findings are the first to indicate that a single seven-transmembrane receptor can switch recognition as well as function with certain chemotactic peptides to inhibitory with ATL and LX (lipid ligands). Moreover, they suggest that ALXR activation by LX or ATL can protect the host from potentially deleterious PMN responses associated with innate immunity as well as direct effector responses in tissue injury by recognition of peptide fragments.

Key Words: inhibitory receptors • antiinflammation • resolution • leukocytes • MHC binding peptide

International Union of Pharmacologic Sciences (IUPHAR) Nomenclature Committee, Dahlén et al. Receptor Compendium: Leukotriene Receptors, Stockholm, Sweden, November 1999.

Abbreviations used in this paper: ALXR, lipoxin A4 receptor; ATL, aspirin-triggered 15-epi-LXA4; ATLa, ATL analogue(s) [ATLa1: 15(R/S)-methyl-LXA4 methyl ester; ATLa2: 15-epi-16-(para-fluoro)-phenoxy-LXA4 methyl ester]; BLT, leukotriene B4 receptor; CHO, Chinese hamster ovary; FPR, N-formyl peptide receptor; HEK, human embryonic kidney; LX, lipoxin; LXA4, 5(S),6(R),15(S)-trihydroxy-7,9,13-trans-11-cis eicosatetraenoic acid; SAA, serum amyloid protein A.

© 2000 The Rockefeller University Press


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