The Journal of Experimental Medicine
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Published 17 February 2004. doi:10.1084/jem.20031325
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 4, 515-523
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Exogenous Pathogen and Plant 15-Lipoxygenase Initiate Endogenous Lipoxin A4 Biosynthesis

Gerard L. Bannenberg1, Julio Aliberti2, Song Hong1, Alan Sher2, and Charles Serhan1

1 Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115
2 Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892

Address correspondence to C.N. Serhan, Center for Experimental Therapeutics and Reperfusion Injury, Dept. of Anesthesiology, Perioperative and Pain Medicine, Thorn Medical Research Building, 7th Fl., Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115. Phone: (617) 732-8820; Fax: (617) 278-6957; email: cnserhan{at}zeus.bwh.harvard.edu

Lipoxin A4 (LXA4) is a potent endogenous lipoxygenase-derived eicosanoid with antiinflammatory and proresolving properties. Supraphysiological levels of LXA4 are generated during infection by Toxoplasma gondii, which in turn reduces interleukin (IL) 12 production by dendritic cells, thus dampening Th1-type cell-mediated immune responses and host immunopathology. In the present work, we sought evidence for the structural basis of T. gondii's ability to activate LXA4 biosynthesis. Proteomic analysis of T. gondii extract (soluble tachyzoite antigen [STAg]), which preserves the immunosuppressive and antiinflammatory activity of the parasite, yielded several peptide matches to known plant lipoxygenases. Hence, we incubated STAg itself with arachidonic acid and found using LC-UV-MS-MS–based lipidomics that STAg produced both 15-HETE and 5,15-diHETE, indicating that T. gondii carries 15-lipoxygenase activity. In addition, T. gondii tachyzoites (the rapidly multiplying and invasive stage of the parasite) generated LXA4 when provided with arachidonic acid. Local administration of a plant (soybean) lipoxygenase itself reduced neutrophilic infiltration in murine peritonitis, demonstrating that 15-lipoxygenase possesses antiinflammatory properties. Administration of plant 15-lipoxygenase generated endogenous LXA4 and mimicked the suppression of IL-12 production by splenic dendritic cells observed after T. gondii infection or STAg administration. Together, these results indicate that 15-lipoxygenase expressed by a pathogen as well as exogenously administered 15-lipoxygenase can interact with host biosynthetic circuits for endogenous "stop signals" that divert the host immune response and limit acute inflammation.

Key Words: antiinflammation • transcellular biosynthesis • lipid mediators • Toxoplasma gondii • leukocytes

Abbreviations used in this paper: DPBS, Dulbecco's phosphate buffered saline; LXA4, lipoxin A4; STAg, soluble tachyzoite antigen.


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