Cyclooxygenase-1 orchestrates germinal center formation and antibody class-switch via regulation of IL-17.
Cyclooxygenase-1 orchestrates germinal center formation and antibody class-switch via regulation of IL-17.
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DOI：
10.4049/jimmunol.0901499
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发表时间：
2009-11-01
期刊：
影响因子：
--
通讯作者：
Brown CR
中科院分区：
文献类型：
--
作者：
Blaho VA;Buczynski MW;Dennis EA;Brown CR
环氧化酶（COX）是先天性免疫细胞功能的已知调节因子；然而，它们对适应性免疫的作用相对未知。我们研究了COX - 1和COX - 2在对莱姆病病原体伯氏疏螺旋体感染的体液免疫应答中的作用。我们报告称，在体外，小鼠B细胞组成性表达COX - 1，并且在受到伯氏疏螺旋体或抗CD40刺激后，COX - 1和COX - 2以及它们的产物前列腺素E2（PGE2）、前列腺素F2α（PGF2α）和血栓素B2（TXB2）及其受体的表达上调。在体外抑制小鼠B细胞中的COX - 1和/或COX - 2会导致类花生酸产生减少以及抗体产生改变。重要的是，缺乏COX - 1（而非COX - 2活性）的小鼠感染后会导致免疫球蛋白类别转换缺陷以及缺乏伯氏疏螺旋体特异性IgG产生。这种缺陷与生发中心形成减少以及白细胞介素 - 6（IL - 6）和白细胞介素 - 17（IL - 17）产生减少相关，并且可以通过恢复IL - 6部分恢复，但通过IL - 17可完全恢复。此外，用COX - 1抑制剂处理的小鼠的血清在杀伤伯氏疏螺旋体方面效果显著降低，但在给予IL - 17的用COX - 1抑制剂处理的小鼠中，杀螺旋体活性得以恢复。我们得出结论，IL - 17在感染应答中的抗体产生和免疫球蛋白类别转换中起作用，并且COX - 1是这种应答的一个关键的、先前未被认识的调节因子。
The cyclooxygenase (COX) enzymes are known modulators of innate immune cell function; however, their contributions to adaptive immunity are relatively unknown. We investigated the roles of COX-1 and COX-2 in the humoral immune response to infection with the Lyme disease pathogen, Borrelia burgdorferi. We report that in vitro, murine B cells constitutively expressed COX-1 and up-regulated expression of both COX-1 and COX-2 as well as their products PGE2, PGF2α and TXB2 and their receptors following stimulation with B. burgdorferi or anti-CD40. In vitro inhibition of COX-1 and/or COX-2 in murine B cells resulted in decreased eicosanoid production, and altered antibody production. Importantly, infection of mice lacking COX-1, but not COX-2 activity resulted in a defect in immunoglobulin class-switching and a lack of Borrelia-specific IgG production. This defect correlated with decreased germinal center formation and IL-6 and IL-17 production, and could be partially recovered by restoration of IL-6, but fully recovered by IL-17. Furthermore, sera from COX-1 inhibitor-treated mice were dramatically less effective in killing B. burgdorferi, but borreliacidal activity was restored in COX-1 inhibitor-treated mice administered IL-17. We conclude that IL-17 plays a role in antibody production and immunoglobulin class-switching in response to infection and that COX-1 is a critical, previously unrecognized regulator of this response.
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