Patel Manish, Xu Damo, Kewin Pete, Choo-Kang Brian, McSharry Charles, Thomson Neil C, Liew Foo Y
Division of Immunology, Infection and Inflammation, University of Glasgow, Glasgow, Scotland, United Kingdom.
J Immunol. 2005 Jun 15;174(12):7558-63. doi: 10.4049/jimmunol.174.12.7558.
TLRs are primary sensors of both innate and adaptive immune systems, where they play a pivotal role in the response directed against structurally conserved components of pathogens. Synthetic bacterial lipopeptide Pam3CSK4 is a TLR2 agonist capable of modulating Th1 and Th2 responses. This study examines the therapeutic effect of Pam3CSK4 in established airway inflammation in a murine model of asthma. In mice previously sensitized and challenged with OVA, Pam3CSK4 given i.p. markedly reduced the total inflammatory cell infiltrate and eosinophilia in bronchoalveolar lavage fluid. Pam3CSK4 therapy was associated with a reduction in OVA-induced IL-4 and IL-5 secretion from thoracic lymph node culture, airways inflammation, bronchial hyperresponsiveness, and serum levels of IgE. Pam3CSK4 therapy was also associated with an increase in OVA-induced IFN-gamma, IL-12, and IL-10 production. However, the anti-inflammatory effect of Pam3CSK4 was independent of IL-10 or TGF-beta, but was critically dependent on IL-12, the production of which by dendritic cells was enhanced by Pam3CSK4 in vitro. Our results provide direct evidence that Pam3CSK4 could represent a novel therapeutic agent in allergic airways disease.
Toll样受体（TLRs）是先天性和适应性免疫系统的主要传感器，在针对病原体结构保守成分的反应中发挥关键作用。合成细菌脂肽Pam3CSK4是一种能够调节Th1和Th2反应的TLR2激动剂。本研究在哮喘小鼠模型中研究了Pam3CSK4对已建立的气道炎症的治疗作用。在先前用卵清蛋白（OVA）致敏和激发的小鼠中，腹腔注射Pam3CSK4可显著减少支气管肺泡灌洗液中的总炎症细胞浸润和嗜酸性粒细胞增多。Pam3CSK4治疗与OVA诱导的胸段淋巴结培养物中IL-4和IL-5分泌减少、气道炎症、支气管高反应性以及血清IgE水平降低有关。Pam3CSK4治疗还与OVA诱导的IFN-γ、IL-12和IL-10产生增加有关。然而，Pam3CSK4的抗炎作用不依赖于IL-10或TGF-β，而是关键依赖于IL-12，Pam3CSK4在体外可增强树突状细胞产生IL-12。我们的结果提供了直接证据，表明Pam3CSK4可能是过敏性气道疾病中的一种新型治疗药物。
