Cyclooxygenase 2 pathway and its therapeutic inhibition in superantigen-induced toxic shock.
Cyclooxygenase 2 pathway and its therapeutic inhibition in superantigen-induced toxic shock.
复制标题
环加氧酶 2 途径及其对超抗原诱导的中毒性休克的治疗抑制。
DOI：
10.1097/shk.0b013e31817048f7
复制
发表时间：
2008
期刊：
影响因子：
--
通讯作者：
David,ChellaS
中科院分区：
文献类型：
--
作者：
Rajagopalan,Govindarajan;Asmann,YanW;Lytle,AnnaK;Tilahun,AshenafiY;Theuer,JayneE;Smart,MicheleK;Patel,Robin;David,ChellaS
细菌超抗原是一个外毒素家族，是已知最有效的T细胞激活剂。由于它们能够诱导强烈的免疫激活，超抗原已经涉及从自限性食物中毒到更严重的中毒性休克综合征（TSS）的多种疾病，并且具有用作生物恐怖主义试剂的潜力。尽管如此，超抗原激活T细胞导致急性全身炎症反应、多器官功能障碍和最终死亡的确切分子机制尚不清楚。对发病机制的认识不足，导致缺乏有效的治疗超抗原诱导的TSS的发展。为了弥补这些不足，我们利用人源化人类白细胞抗原-DR 3转基因小鼠模型，通过基于基因芯片的基因表达谱分析，系统地剖析了超抗原诱导的TSS的分子发病机制。在全身性超抗原（葡萄球菌肠毒素B [SE B]）暴露后不久，脾脏中的胰高血糖素-内过氧化物合酶2（PTGS-2;也称为环氧合酶2或考克斯-2）基因表达增加了数百倍。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被SEB显著调节。考虑到考克斯-2通路在炎症中的重要性，我们研究了通过高选择性抑制剂CAY 10404治疗性抑制考克斯-2是否有益。我们的研究表明，在用10 μg SEB攻击后立即ip给予CAY 10404（50 mg/kg）不能抑制SEB诱导的体内细胞因子/趋化因子产生或T细胞活化/增殖，并且不能防止超抗原相关的胸腺细胞凋亡。
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 ip administration of CAY10404 (50 mg/kg) immediately after challenge with 10 μg 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.