Division of Allergy and Infectious Diseases, University of Washington, Seattle, WA 98195, USA.
J Immunol. 2012 Aug 15;189(4):1737-46. doi: 10.4049/jimmunol.1103541. Epub 2012 Jul 9.
Tuberculosis, one of the leading causes of death worldwide, stimulates inflammatory responses with beneficial and pathologic consequences. The regulation and nature of an optimal inflammatory response to Mycobacterium tuberculosis remains poorly understood in humans. Insight into mechanisms of negative regulation of the TLR-mediated innate immune response to M. tuberculosis could provide significant breakthroughs in the design of new vaccines and drugs. We hypothesized that TOLLIP and its common variants negatively regulate TLR signaling in human monocytes and are associated with susceptibility to tuberculosis. Using short hairpin RNA knockdown of TOLLIP in peripheral blood human monocytes, we found that TOLLIP suppresses TNF and IL-6 production after stimulation with TLR2 and TLR4 ligands. In contrast, secretion of the anti-inflammatory cytokine IL-10 was induced by TOLLIP. We also discovered two common polymorphisms that are associated with either decreased levels of mRNA expression (rs3750920) or increased IL-6 production (rs5743899) in a sample of 56 healthy volunteers. Furthermore, in a case-population study in Vietnam with 760 cord blood samples and 671 TB case patients, we found that SNPs rs3750920 and rs5743899 were associated with susceptibility to tuberculosis (p = 7.03 × 10(-16) and 6.97 × 10(-7), respectively). These data demonstrate that TOLLIP has an anti-inflammatory effect on TLR signaling in humans and that TOLLIP deficiency is associated with an increased risk of tuberculosis. To our knowledge, these data also show the first associations of TOLLIP polymorphisms with any infectious disease. These data also implicate an unexpected mechanism of negative regulation of TLR signaling in human tuberculosis pathogenesis.
结核病是全球主要死因之一，它会引发有益和有害的炎症反应。人类对结核分枝杆菌（Mycobacterium tuberculosis）的最佳炎症反应的调节和性质仍未得到很好的理解。深入了解 TLR 介导的先天免疫对结核分枝杆菌反应的负调控机制，可能会在设计新型疫苗和药物方面取得重大突破。我们假设 TOLLIP 及其常见变异体负调控人类单核细胞中 TLR 信号，并与结核病易感性相关。通过对人外周血单核细胞中的 TOLLIP 进行短发夹 RNA 敲低，我们发现 TOLLIP 可抑制 TLR2 和 TLR4 配体刺激后的 TNF 和 IL-6 产生。相反，TOLLIP 可诱导抗炎细胞因子 IL-10 的分泌。我们还发现了两个常见的多态性，它们与健康志愿者样本中 mRNA 表达水平降低（rs3750920）或 IL-6 产生增加（rs5743899）相关。此外，在越南进行的一项包含 760 份脐带血样本和 671 例结核病患者的病例-对照研究中，我们发现 rs3750920 和 rs5743899 与结核病易感性相关（p = 7.03×10(-16)和 6.97×10(-7)）。这些数据表明，TOLLIP 对人类 TLR 信号具有抗炎作用，TOLLIP 缺乏与结核病风险增加相关。据我们所知，这些数据还首次显示了 TOLLIP 多态性与任何传染病的关联。这些数据还表明，在人类结核病发病机制中存在 TLR 信号负调控的意外机制。
