Bannenberg Gerard L, Aliberti Julio, Hong Song, Sher Alan, Serhan Charles
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.
J Exp Med. 2004 Feb 16;199(4):515-23. doi: 10.1084/jem.20031325.
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.
脂氧素A4（LXA4）是一种由脂氧合酶产生的具有抗炎和促炎症消退特性的强效内源性类二十烷酸。在感染刚地弓形虫期间会产生超生理水平的LXA4，这反过来会减少树突状细胞产生白细胞介素（IL）-12，从而抑制Th1型细胞介导的免疫反应和宿主免疫病理学。在本研究中，我们寻找刚地弓形虫激活LXA4生物合成能力的结构基础的证据。对保留了寄生虫免疫抑制和抗炎活性的刚地弓形虫提取物（可溶性速殖子抗原[STAg]）进行蛋白质组分析，得到了与已知植物脂氧合酶的几个肽段匹配结果。因此，我们将STAg本身与花生四烯酸一起孵育，并使用基于液相色谱-紫外-质谱-质谱的脂质组学方法发现STAg产生了15-羟基二十碳四烯酸（15-HETE）和5,15-二羟基二十碳四烯酸（5,15-diHETE），表明刚地弓形虫具有15-脂氧合酶活性。此外，当提供花生四烯酸时，刚地弓形虫速殖子（寄生虫快速繁殖和侵袭阶段）会产生LXA4。局部施用植物（大豆）脂氧合酶本身可减少小鼠腹膜炎中的嗜中性粒细胞浸润，表明15-脂氧合酶具有抗炎特性。施用植物15-脂氧合酶可产生内源性LXA4，并模拟了刚地弓形虫感染或施用STAg后观察到的脾树突状细胞对IL-12产生的抑制作用。总之，这些结果表明病原体表达的15-脂氧合酶以及外源性施用的15-脂氧合酶可以与宿主生物合成途径相互作用，产生内源性“终止信号”，从而改变宿主免疫反应并限制急性炎症。
