Parasite-induced lipoxin A4 is an endogenous regulator of IL-12 production and immunopathology in Toxoplasma gondii infection

被引:166
作者
Aliberti, J
Serhan, C
Sher, A
机构
[1] NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA
[2] Harvard Univ, Brigham & Womens Hosp, Ctr Expt Therapeut & Reperfus Injury, Dept Anesthesiol Perioperat & Pain Res,Sch Med, Boston, MA 02115 USA
关键词
Toxoplasma gondii; interleukin-12; eicosanoid; lipoxygenase; lipoxin A(4);
D O I
10.1084/jem.20021183
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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)A(4), 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 LXA(4) 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 LXA(4) 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.
引用
收藏
页码:1253 / 1262
页数:10
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