The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1997/5/1693/ $5.00
The Journal of Experimental Medicine, Volume 185, Number 9, May 5, 1997 1693-1704

Articles

Aspirin-triggered 15-Epi-Lipoxin A4 (LXA4) and LXA4 Stable Analogues Are Potent Inhibitors of Acute Inflammation: Evidence for Anti-inflammatory Receptors

Tomoko Takano*,{ddagger}, Stefano Fiore*, Jane F. Maddox*, Hugh R. Brady{ddagger}, Nicos A. Petasis§, and Charles N. Serhan*

From the * Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesia, and the {ddagger} Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115; and the § Department of Chemistry, University of Southern California, Los Angeles, California 90089

Lipoxins are bioactive eicosanoids that are immunomodulators. In human myeloid cells, lipoxin (LX) A4 actions are mediated by interaction with a G protein–coupled receptor. To explore functions of LXA4 and aspirin-triggered 5(S),6(R),15(R)-trihydroxy-7,9,13-trans-11-cis–eicosatetraenoic acid (15-epi-LXA4) in vivo, we cloned and characterized a mouse LXA4 receptor (LXA4R). When expressed in Chinese hamster ovary cells, the mouse LXA4R showed specific binding to [3H]LXA4 (Kd {approx} 1.5 nM), and with LXA4 activated GTP hydrolysis. Mouse LXA4R mRNA was most abundant in neutrophils. In addition to LXA4 and 15-epi-LXA4, bioactive LX stable analogues competed with both [3H]LXA4 and [3H]leukotriene D4 (LTD4)– specific binding in vitro to neutrophils and endothelial cells, respectively. Topical application of LXA4 analogues and novel aspirin-triggered 15-epi-LXA4 stable analogues to mouse ears markedly inhibited neutrophil infiltration in vivo as assessed by both light microscopy and reduced myeloperoxidase activity in skin biopsies. The 15(R)-16-phenoxy-17,18, 19,20-tetranorLXA4 methyl ester (15-epi-16-phenoxy-LXA4), an analogue of aspirin triggered 15-epi-LXA4, and 15(S)-16-phenoxy-17,18,19,20-tetranor-LXA4 methyl ester (16-phenoxy-LXA4) were each as potent as equimolar applications of the anti-inflammatory, dexamethasone. Thus, we identified murine LXA4R, which is highly expressed on murine neutrophils, and showed that both LXA4 and 15-epi-LXA4 stable analogues inhibit neutrophil infiltration in the mouse ear model of inflammation. These findings provide direct in vivo evidence for an anti-inflammatory action for both aspirin-triggered LXA4 and LXA4 stable analogues and their site of action in vivo.

Address correspondence to C.N. Serhan, Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115. Dr. Fiore's current address is Section of Rheumatology, University of Illinois at Chicago Medical College, Chicago, IL 60607. Dr. Brady's present address is University College Dublin, Mater Miseracordiae Hospital, Dublin, Ireland.

This work was presented in part at the American Society of Nephrology, New Orleans, November 1996.

1 Abbreviations used in this paper: CHO, Chinese hamster ovary cell; DPBS, Dulbecco's phosphate-buffered saline; LO, lipoxygenase; LTB4, leukotriene B4; LTD4, leukotriene D4; lipoxin A4 (LXA4), 5(S),6(R),15(S)-trihydroxy7,9,13-trans-11-cis-eicosatetraenoic acid; 15-epi-LXA4, 5(S),6(R),15(R)- trihydroxy-7,9,13-trans-11-cis-eicosatetraenoic acid; 15(R/S)-methyl-LXA4, 5(S),6(R), 15(R/S)-trihydroxy-15-methyl-7,9,13-trans-11-cis-eicosatetraenoic acid; 16-phenoxy-LXA4, 15(S)-16-phenoxy-17,18,19,20-tetranor-LXA4 methyl ester; 15-epi-16-phenoxy-LXA4, 15(R)-16-phenoxy-17,18,19,20tetranor-LXA4 methyl ester; 15(R/S)-16-phenoxy-11,12-acetylenic-LXA4, 15(R/S)-16-phenoxy-11,12-acetylenic-17,18,19,20-tetranor-LXA4 methyl ester; LX, lipoxin; MPO, myeloperoxidase; RACE, rapid amplification of cDNA end.


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