Rajagopalan Govindarajan, Asmann Yan W, Lytle Anna K, Tilahun Ashenafi Y, Theuer Jayne E, Smart Michele K, Patel Robin, David Chella S
Department of Immunology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
Shock. 2008 Dec;30(6):721-8. doi: 10.1097/SHK.0b013e31817048f7.
Bacterial superantigens are a family of exotoxins that are the most potent T-cell activators known. Because of their ability to induce strong immune activation, superantigens have been implicated in a variety of diseases ranging from self-limiting food poisoning to more severe toxic shock syndrome (TSS) and have the potential to be used as agents of bioterrorism. Nonetheless, the precise molecular mechanisms by which T-cell activation by superantigens lead to acute systemic inflammatory response, multiple organ dysfunction, and ultimately death are unclear. Inadequate understanding of the pathogenesis has resulted in lack of development of effective therapy for superantigen-induced TSS. To fill these deficiencies, we systematically dissected the molecular pathogenesis of superantigen-induced TSS using the humanized human leukocyte antigen-DR3 transgenic mouse model by microarray-based gene expression profiling. Splenic expression of prostaglandin-endoperoxide synthase 2 (PTGS-2; also called cyclooxygenase 2 or COX-2) gene was increased by several hundred folds shortly after systemic superantigen (staphylococcal enterotoxin B [SEB]) exposure. In addition, expressions of several genes associated with eicosanoid pathway were significantly modulated by SEB, as analyzed by dedicated software. Given the importance of the COX-2 pathway in inflammation, we examined whether therapeutic inhibition of COX-2 by a highly selective inhibitor, CAY10404, could be beneficial. Our studies showed that i.p. administration of CAY10404 (50 mg/kg) immediately after challenge with 10 microg of SEB was unable to inhibit SEB-induced in vivo cytokine/chemokine production or T-cell activation/proliferation and did not prevent superantigen-associated thymocyte apoptosis.
细菌超抗原是一类外毒素，是已知最强效的T细胞激活剂。由于其能够诱导强烈的免疫激活，超抗原已被认为与多种疾病有关，从自限性食物中毒到更严重的中毒性休克综合征（TSS），并且有可能被用作生物恐怖主义制剂。然而，超抗原激活T细胞导致急性全身炎症反应、多器官功能障碍并最终导致死亡的确切分子机制尚不清楚。对发病机制的认识不足导致缺乏针对超抗原诱导的TSS的有效治疗方法。为了填补这些空白，我们使用基于微阵列的基因表达谱分析的人源化人类白细胞抗原-DR3转基因小鼠模型，系统地剖析了超抗原诱导的TSS的分子发病机制。全身暴露于超抗原（葡萄球菌肠毒素B [SEB]）后不久，脾脏中前列腺素内过氧化物合酶2（PTGS-2；也称为环氧化酶2或COX-2）基因的表达增加了数百倍。此外，通过专用软件分析，与类花生酸途径相关的几个基因的表达受到SEB的显著调节。鉴于COX-2途径在炎症中的重要性，我们研究了高选择性抑制剂CAY10404对COX-2的治疗性抑制是否有益。我们的研究表明，在用10微克SEB攻击后立即腹腔注射CAY10404（50毫克/千克）无法抑制SEB诱导的体内细胞因子/趋化因子产生或T细胞激活/增殖，也不能预防超抗原相关的胸腺细胞凋亡。
