The Journal of Experimental Medicine
Keystone Symposia
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Published 4 November 2002. doi:10.1084/jem.20021183
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© Rockefeller University Press, 0022-1007/2002/11/1253 $5.00
The Journal of Experimental Medicine, Volume 196, Number 9, 1253-1262

Parasite-induced Lipoxin A4 Is an Endogenous Regulator of IL-12 Production and Immunopathology in Toxoplasma gondii Infection

Julio Aliberti1, Charles Serhan2 and Alan Sher1

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

Address correspondence to Julio Aliberti, Immunobiology Section, Laboratory of Parasitic Diseases, NIAID/NIH, 50 South Drive, MSC 8003, Bethesda, MD 20892. Phone: 301-402-9489; Fax: 301-402-0890; E-mail: jaliberti{at}niaid.nih.gov

The production of interleukin (IL)-12 is critical for the development of interferon (IFN)-{gamma}–dependent resistance to Toxoplasma gondii. Nevertheless, when this response is dysregulated, such as occurs in the absence of IL-10, the uncontrolled inflammation that results can have lethal consequences for the host. Recently, we demonstrated that lipoxin (LX)A4, an eicosanoid mediator that depends on 5-lipoxygenase (LO) for its biosynthesis, exerts a regulatory role on dendritic cell IL-12 production triggered artificially by a T. gondii extract. We now formally establish the physiological relevance of this pathway in the systemic control of IL-12 production induced by live T. gondii infection and demonstrate its function to be distinct from that of IL-10. Thus, T. gondii–exposed wild-type, but not 5-LO–deficient animals, produced high levels of serum LXA4 beginning at the onset of chronic infection. Moreover, 5-LO-/-, in contrast to wild-type mice, succumbed during the same period displaying a marked encephalitis. The increased mortality of the 5-LO-/- animals was also associated with significant elevations of IL-12 and IFN-{gamma} and was completely prevented by the administration of a stable LXA4 analogue. Together, these findings demonstrate a new pathway involving the induction of host LXs for the in vivo regulation of proinflammatory responses during microbial infection.

Key Words: Toxoplasma gondii • interleukin-12 • eicosanoid • lipoxygenase • lipoxin A4


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