Department of Academic Surgery, University College Cork/National University of Ireland, Cork University Hospital, Cork, Ireland.
J Immunol. 2010 May 15;184(10):5802-8. doi: 10.4049/jimmunol.0904127. Epub 2010 Apr 16.
Activation of TLR signaling is critical for host innate immunity against bacterial infection. Previous studies reported that the ST2 receptor, a member of the Toll/IL-1 receptor superfamily, functions as a negative regulator of TLR4 signaling and maintains LPS tolerance. However, it is undetermined whether ST2 negatively regulates TLR2 signaling and furthermore, whether a TLR2 agonist, bacterial lipoprotein (BLP)-induced tolerance is dependent on ST2. In this study, we show that BLP stimulation-induced production of proinflammatory cytokines and immunocomplex formation of TLR2-MyD88 and MyD88-IL-1R-associated kinase (IRAK) were significantly enhanced in ST2-deficient macrophages compared with those in wild-type controls. Furthermore, overexpression of ST2 dose-dependently attenuated BLP-induced NF-kappaB activation, suggesting a negative regulatory role of ST2 in TLR2 signaling. A moderate but significantly attenuated production of TNF-alpha and IL-6 on a second BLP stimulation was observed in BLP-pretreated, ST2-deficient macrophages, which is associated with substantially reduced IRAK-1 protein expression and downregulated TLR2-MyD88 and MyD88-IRAK immunocomplex formation. ST2-deficient mice, when pretreated with a nonlethal dose of BLP, benefitted from an improved survival against a subsequent lethal BLP challenge, indicating BLP tolerance develops in the absence of the ST2 receptor. Taken together, our results demonstrate that ST2 acts as a negative regulator of TLR2 signaling, but is not required for BLP-induced tolerance.
TLR 信号的激活对于宿主固有免疫抵抗细菌感染至关重要。先前的研究报道，Toll/IL-1 受体超家族的成员 ST2 受体作为 TLR4 信号的负调节剂，维持 LPS 耐受。然而，ST2 是否负调节 TLR2 信号，以及 TLR2 激动剂、细菌脂蛋白 (BLP) 诱导的耐受是否依赖于 ST2，尚不确定。在这项研究中，我们表明，与野生型对照相比，BLP 刺激诱导的前炎性细胞因子产生和 TLR2-MyD88 和 MyD88-IL-1R 相关激酶 (IRAK) 的免疫复合物形成在 ST2 缺陷型巨噬细胞中显著增强。此外，ST2 的过表达剂量依赖性地减弱了 BLP 诱导的 NF-κB 激活，表明 ST2 在 TLR2 信号中具有负调节作用。在 BLP 预处理的 ST2 缺陷型巨噬细胞中，观察到第二次 BLP 刺激时 TNF-α和 IL-6 的产生适度但显著减弱，这与 IRAK-1 蛋白表达显著减少以及 TLR2-MyD88 和 MyD88-IRAK 免疫复合物形成下调有关。在预先用非致死剂量的 BLP 处理的 ST2 缺陷型小鼠中，对随后的致死性 BLP 挑战的存活率得到了改善，表明在没有 ST2 受体的情况下会产生 BLP 耐受。总之，我们的结果表明，ST2 作为 TLR2 信号的负调节剂，但不是 BLP 诱导耐受所必需的。
