Goodridge H S, Wilson E H, Harnett W, Campbell C C, Harnett M M, Liew F Y
Department of Immunology and Bacteriology, University of Glasgow, Western Infirmary, Dumbarton Road, Glasgow G11 6NT, United Kingdom.
J Immunol. 2001 Jul 15;167(2):940-5. doi: 10.4049/jimmunol.167.2.940.
Parasite survival and host health may depend on the ability of the parasite to modulate the host immune response by the release of immunomodulatory molecules. Excretory-secretory (ES)-62, one such well-defined molecule, is a major secreted protein of the rodent filarial nematode Acanthocheilonema viteae, and has homologues in human filarial nematodes. Previously we have shown that ES-62 is exclusively associated with a Th2 Ab response in mice. Here we provide a rationale for this polarized immune response by showing that the parasite molecule suppresses the IFN-gamma/LPS-induced production, by macrophages, of bioactive IL-12 (p70), a key cytokine in the development of Th1 responses. This suppression of the induction of a component of the host immune response extends to the production of the proinflammatory cytokines IL-6 and TNF-alpha, but not NO. The molecular mechanism underlying these findings awaits elucidation but, intriguingly, the initial response of macrophages to ES-62 is to demonstrate a low and transient release of these cytokines before becoming refractory to further release induced by IFN-gamma/LPS. The relevance of our observations is underscored by the finding that macrophages recovered from mice exposed to "physiological" levels of ES-62 by the novel approach of continuous release from implanted osmotic pumps in vivo were similarly refractory to release of IL-12, TNF-alpha, IL-6, but not NO, ex vivo. Therefore, our results suggest that exposure to ES-62 renders macrophages subsequently unable to produce Th1/proinflammatory cytokines. This likely contributes to the generation of immune responses with an anti-inflammatory Th2 phenotype, a well-documented feature of filarial nematode infection.
寄生虫的存活以及宿主的健康状况可能取决于寄生虫通过释放免疫调节分子来调节宿主免疫反应的能力。排泄分泌（ES）-62就是这样一种明确的分子，它是啮齿类丝状线虫旋盘尾丝虫的一种主要分泌蛋白，在人类丝状线虫中也有同源物。此前我们已经表明，ES-62在小鼠中仅与Th2抗体反应相关。在此，我们通过证明这种寄生虫分子抑制巨噬细胞由干扰素-γ/脂多糖诱导产生具有生物活性的白细胞介素-12（p70）（Th1反应发展中的关键细胞因子），为这种极化免疫反应提供了理论依据。对宿主免疫反应一个组成部分诱导的这种抑制作用还延伸至促炎细胞因子白细胞介素-6和肿瘤坏死因子-α的产生，但不包括一氧化氮。这些发现背后的分子机制有待阐明，但有趣的是，巨噬细胞对ES-62的初始反应是在对干扰素-γ/脂多糖诱导的进一步释放变得不应答之前，短暂且少量地释放这些细胞因子。从通过体内植入渗透泵持续释放“生理”水平的ES-62而暴露于其中的小鼠体内回收的巨噬细胞，在体外同样对白细胞介素-12、肿瘤坏死因子-α、白细胞介素-6的释放不应答，但对一氧化氮的释放并非如此，这一发现突出了我们观察结果的相关性。因此，我们的结果表明，暴露于ES-62会使巨噬细胞随后无法产生Th1/促炎细胞因子。这可能有助于产生具有抗炎性Th2表型的免疫反应，这是丝状线虫感染的一个有充分记录的特征。
