Laboratorio de Biología Experimental, Centro de Estudios Metabólicos, CP 39005 Santander, Spain.
Cytokine. 2013 Feb;61(2):491-8. doi: 10.1016/j.cyto.2012.10.027. Epub 2012 Nov 28.
Osteopontin (OPN) is a multifunctional protein participating in the regulation of different Th cell lineages and critically involved in the initiation of immune responses to diverse pathogens. Our study goal was to verify whether OPN helps modulate the protective Th1 and Th17 cytokine responses in C57BL/6 mice infected with Trypanosoma cruzi, the etiological agent of Chagas disease. Parasite infection induced OPN release from murine macrophages in vitro and acute Chagas mice displayed enhanced serum levels of this cytokine at the peak of parasitemia. Upon administration of a neutralizing anti-OPN antibody, recently infected mice presented lower Th1 and Th17 responses, increased parasitemia and succumbed earlier and at higher rates to infection than non-immune IgG-receiving controls. The anti-OPN therapy also resulted in reduced circulating levels of IL-12 p70, IFN-γ, IL-17A and specific IgG(2a) antibodies. Furthermore, antibody-mediated blockade of OPN activity abrogated the ex vivo production of IL-12 p70, IFN-γ and IL-17A, while promoting IL-10 secretion, by spleen macrophages and CD4(+) T cells from T. cruzi-infected mice. Th1 and Th17 cytokine release induced by OPN preferentially involved the α(v)β(3) integrin OPN receptor, whereas concomitant down-modulation of IL-10 production would mostly depend on OPN interaction with CD44. Our findings suggest that, in resistant C57BL/6 mice, elicitation of protective Th1 and Th17 cytokine responses to T. cruzi infection is likely to be regulated by endogenous OPN.
骨桥蛋白（OPN）是一种多功能蛋白，参与调节不同的 Th 细胞谱系，并在启动对多种病原体的免疫反应中起关键作用。我们的研究目的是验证 OPN 是否有助于调节感染克氏锥虫（恰加斯病的病原体）的 C57BL/6 小鼠中的保护性 Th1 和 Th17 细胞因子反应。寄生虫感染在体外诱导鼠巨噬细胞释放 OPN，急性恰加斯病小鼠在寄生虫血症高峰期显示出该细胞因子血清水平增强。在用中和抗 OPN 抗体进行治疗后，新近感染的小鼠表现出较低的 Th1 和 Th17 反应、较高的寄生虫血症以及更早和更高的死亡率感染比非免疫 IgG 接受对照。抗 OPN 治疗还导致循环 IL-12 p70、IFN-γ、IL-17A 和特异性 IgG（2a）抗体水平降低。此外，抗体介导的 OPN 活性阻断消除了脾巨噬细胞和来自 T. cruzi 感染小鼠的 CD4（+）T 细胞体外产生的 IL-12 p70、IFN-γ 和 IL-17A，同时促进 IL-10 分泌。OPN 诱导的 Th1 和 Th17 细胞因子释放主要涉及α（v）β（3）整合素 OPN 受体，而同时下调 IL-10 产生则主要取决于 OPN 与 CD44 的相互作用。我们的研究结果表明，在抗性 C57BL/6 小鼠中，对 T. cruzi 感染产生保护性 Th1 和 Th17 细胞因子反应可能受到内源性 OPN 的调节。
