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

Bannenberg GL, Aliberti J, Hong S, Sher A, Serhan C - J. Exp. Med. (2004)

Bottom Line: 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.Local administration of a plant (soybean) lipoxygenase itself reduced neutrophilic infiltration in murine peritonitis, demonstrating that 15-lipoxygenase possesses antiinflammatory properties.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.

View Article: PubMed Central - PubMed

Affiliation: 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.

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.

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Hypothetical scheme for bidirectional microbial and plant 15-lipoxygenase–initiated biosynthetic pathways that enhance endogenous LXA4 formation.
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fig6: Hypothetical scheme for bidirectional microbial and plant 15-lipoxygenase–initiated biosynthetic pathways that enhance endogenous LXA4 formation.

Mentions: Third, we found that intact T. gondii tachyzoites can form LXA4 in the presence of arachidonic acid. The parasite 15-lipoxygenase could contribute to part of LXA4 biosynthesis in vivo as a result of infection by catalyzing the first step of lipoxin biosynthesis, a scenario that would require a host 5-lipoxygenase for conversion of 15-HETE to LXA4 (Fig. 6). Indeed, 5-lipoxygenase–deficient mice are incapable of producing LXA4 during T. gondii infection, and dendritic cell paralysis does not occur (10). The requirement for exogenously supplied arachidonic acid suggests that tachyzoites do depend on host cell arachidonic acid for the parasite-stimulated LXA4 biosynthesis (Fig. 6). T. gondii infection of macrophages stimulates 15- and 12-HETE, the formation of which is dependent on the incorporation of live tachyzoites into the host cells (30). T. gondii tachyzoites may also trigger the release of arachidonic acid from host phospholipid stores, which is subsequently used for lipoxin biosynthesis. STAg can induce dendritic cell paralysis in vivo, but not in isolated dendritic cells in vitro, indicating that host 5-lipoxygenase activity is likely to be contained in another cell type in the spleen. Treatment of mice with STAg markedly increases the number of 5-lipoxygenase–containing resident macrophages in the spleen (10), suggesting that resident macrophages or newly recruited monocytes can use T. gondii–derived 15-HETE as a substrate to form LXA4. In addition, a T. gondii lipoxygenase could use host 5-lipoxygenase–derived leukotriene A4 as a substrate to generate LXA4 (22).


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

Bannenberg GL, Aliberti J, Hong S, Sher A, Serhan C - J. Exp. Med. (2004)

Hypothetical scheme for bidirectional microbial and plant 15-lipoxygenase–initiated biosynthetic pathways that enhance endogenous LXA4 formation.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2211821&req=5

fig6: Hypothetical scheme for bidirectional microbial and plant 15-lipoxygenase–initiated biosynthetic pathways that enhance endogenous LXA4 formation.
Mentions: Third, we found that intact T. gondii tachyzoites can form LXA4 in the presence of arachidonic acid. The parasite 15-lipoxygenase could contribute to part of LXA4 biosynthesis in vivo as a result of infection by catalyzing the first step of lipoxin biosynthesis, a scenario that would require a host 5-lipoxygenase for conversion of 15-HETE to LXA4 (Fig. 6). Indeed, 5-lipoxygenase–deficient mice are incapable of producing LXA4 during T. gondii infection, and dendritic cell paralysis does not occur (10). The requirement for exogenously supplied arachidonic acid suggests that tachyzoites do depend on host cell arachidonic acid for the parasite-stimulated LXA4 biosynthesis (Fig. 6). T. gondii infection of macrophages stimulates 15- and 12-HETE, the formation of which is dependent on the incorporation of live tachyzoites into the host cells (30). T. gondii tachyzoites may also trigger the release of arachidonic acid from host phospholipid stores, which is subsequently used for lipoxin biosynthesis. STAg can induce dendritic cell paralysis in vivo, but not in isolated dendritic cells in vitro, indicating that host 5-lipoxygenase activity is likely to be contained in another cell type in the spleen. Treatment of mice with STAg markedly increases the number of 5-lipoxygenase–containing resident macrophages in the spleen (10), suggesting that resident macrophages or newly recruited monocytes can use T. gondii–derived 15-HETE as a substrate to form LXA4. In addition, a T. gondii lipoxygenase could use host 5-lipoxygenase–derived leukotriene A4 as a substrate to generate LXA4 (22).

Bottom Line: 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.Local administration of a plant (soybean) lipoxygenase itself reduced neutrophilic infiltration in murine peritonitis, demonstrating that 15-lipoxygenase possesses antiinflammatory properties.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.

View Article: PubMed Central - PubMed

Affiliation: 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.

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.

Show MeSH
Related in: MedlinePlus