Department of Biochemistry and Immunology, University of São Paulo-Ribeirão Preto School of Medicine, Monte Alegre, Ribeirão Preto, São Paulo, Brazil.
J Immunol. 2013 Jul 1;191(1):283-92. doi: 10.4049/jimmunol.1202806. Epub 2013 Jun 3.
Coxsackievirus B (CVB) is a common cause of acute and chronic infectious myocarditis and pancreatitis. Th1 cells producing IFN-γ and TNF-α are important for CVB clearance, but they are also associated with the pathogenesis of inflammatory lesions, suggesting that the modulation of Th1 and Th2 balance is likely important in controlling CVB-induced pancreatitis. We investigated the role of IL-33, which is an important recently discovered cytokine for induction of Th2-associated responses, in experimental CVB5 infection. We found that mice deficient in IL-33R, T1/ST2, significantly developed more severe pancreatitis, had greater weight loss, and contained higher viral load compared with wild-type (WT) mice when infected with CVB5. Conversely, WT mice treated with rIL-33 developed significantly lower viral titers, and pancreatitis was attenuated. Mechanistic studies demonstrated that IL-33 enhances the degranulation and production of IFN-γ and TNF-α by CD8(+) T and NK cells, which is associated with viral clearance. Furthermore, IL-33 triggers the production of IL-4 from mast cells, which results in enhanced differentiation of M2 macrophages and regulatory T cells, leading to the attenuation of inflammatory pancreatitis. Adoptively transferred mast cells or M2 macrophages reversed the heightened pancreatitis in the T1/ST2(-/-) mice. In contrast, inhibition of regulatory T cells exacerbated the disease in WT mice. Together, our findings reveal an unrecognized IL-33/ST2 functional pathway and a key mechanism for CVB5-induced pancreatitis. These data further suggest a novel approach in treating virus-induced pancreatitis, which is a major medical condition with unmet clinical needs.
柯萨奇病毒 B（CVB）是急性和慢性传染性心肌炎和胰腺炎的常见病因。产生 IFN-γ 和 TNF-α 的 Th1 细胞对于 CVB 的清除很重要，但它们也与炎症病变的发病机制有关，这表明调节 Th1 和 Th2 平衡可能对于控制 CVB 诱导的胰腺炎很重要。我们研究了 IL-33 的作用，IL-33 是一种诱导 Th2 相关反应的重要新发现的细胞因子，在实验性 CVB5 感染中。我们发现，与野生型（WT）小鼠相比，缺乏 IL-33R、T1/ST2 的小鼠在感染 CVB5 后明显发展出更严重的胰腺炎，体重减轻更多，病毒载量更高。相反，用 rIL-33 治疗的 WT 小鼠表现出明显较低的病毒滴度，胰腺炎得到减轻。机制研究表明，IL-33 增强了 CD8(+) T 和 NK 细胞的脱颗粒和 IFN-γ 和 TNF-α 的产生，这与病毒清除有关。此外，IL-33 触发肥大细胞产生 IL-4，导致 M2 巨噬细胞和调节性 T 细胞的分化增强，从而减轻炎症性胰腺炎。过继转移的肥大细胞或 M2 巨噬细胞逆转了 T1/ST2(-/-) 小鼠中加重的胰腺炎。相反，抑制调节性 T 细胞会使 WT 小鼠的疾病恶化。总之，我们的研究结果揭示了一个未被认识的 IL-33/ST2 功能途径和 CVB5 诱导的胰腺炎的关键机制。这些数据进一步表明了一种治疗病毒诱导胰腺炎的新方法，这是一种具有未满足临床需求的主要医学病症。
