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PMID: 14970178 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Exogenous pathogen and plant 15-lipoxygenase initiate endogenous lipoxin A4 biosynthesis.

The Journal of experimental medicine ·Vol. 199 ·No. 4 ·2004-02-16 ·Pages 515-23

Bannenberg GL, Aliberti J, Hong S, Sher A, Serhan C

Abstract

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.

MeSH Terms
Animals Arachidonate 15-Lipoxygenase/metabolism Enzyme-Linked Immunosorbent Assay Hydroxyeicosatetraenoic Acids/metabolism Kinetics Lipoxins/biosynthesis Proteome Soybeans/enzymology Toxoplasma/enzymology
Chemicals
Hydroxyeicosatetraenoic Acids Lipoxins Proteome lipoxin A4 15-hydroxy-5,8,11,13-eicosatetraenoic acid Arachidonate 15-Lipoxygenase
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Bannenberg Gerard L
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, USA.
Aliberti Julio
Hong Song
Sher Alan
Serhan Charles
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.20031325
Published
2004-02-16
Pages
515-23
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2211821
Subset
IM
Grants
NIGMS NIH HHS · R01 GM038765 · United States
NIDCR NIH HHS · P01-DE13499 · United States
NIDDK NIH HHS · P01 DK050305 · United States
NIDDK NIH HHS · P01-DK50305 · United States
NIDCR NIH HHS · P01 DE013499 · United States
NIGMS NIH HHS · R37 GM038765 · United States
NIGMS NIH HHS · GM-38765 · United States
External Links
PubMed source DOI: 10.1084/jem.20031325 PMC Full Text View journal details
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