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结核分枝杆菌脂阿拉伯甘露聚糖介导的IRAK-M诱导对巨噬细胞中Toll样受体依赖性白细胞介素-12 p40的产生起负调节作用。

Mycobacterium tuberculosis lipoarabinomannan-mediated IRAK-M induction negatively regulates Toll-like receptor-dependent interleukin-12 p40 production in macrophages.

作者信息

Pathak Sushil Kumar, Basu Sanchita, Bhattacharyya Asima, Pathak Shresh, Kundu Manikuntala, Basu Joyoti

机构信息

Department of Chemistry, Bose Institute, 93/1 Acharya Prafulla Chandra Road, Kolkata 700009, India.

出版信息

J Biol Chem. 2005 Dec 30;280(52):42794-800. doi: 10.1074/jbc.M506471200. Epub 2005 Nov 1.

Abstract

Mannose-capped lipoarabinomannans (Man-LAMs) are members of the repertoire of Mycobacterium tuberculosis modulins that the bacillus uses to subvert the host innate immune response. Interleukin-12 (IL-12) production is critical for mounting an effective immune response by the host against M. tuberculosis. We demonstrate that Man-LAM inhibits IL-12 p40 production mediated by subsequent challenge with lipopolysaccharide (LPS). Man-LAM inhibits LPS-induced IL-12 p40 expression in an IL-10-independent manner. It attenuates LPS-induced NF-kappaB-driven luciferase gene expression, suggesting that its effects are likely directly related to inhibition of NF-kappaB. This is probably because of dampening of the Toll-like receptor signaling. Man-LAM inhibits IL-1 receptor-associated kinase (IRAK)-TRAF6 interaction as well as IkappaB-alpha phosphorylation. It directly attenuates nuclear translocation and DNA binding of c-Rel and p50. Man-LAM exerts these effects by inducing the expression of Irak-M, a negative regulator of TLR signaling. Knockdown of Irak-M expression by RNA interference reinstates LPS-induced IL-12 production in Man-LAM-pretreated cells. The fact that Irak-M expression could be elicited by yeast mannan suggested that ligation of the mannose receptor by the mannooligosaccharide caps of LAM was the probable trigger for IRAK-M induction.

摘要

甘露糖封端的脂阿拉伯甘露聚糖(Man-LAMs)是结核分枝杆菌调节素库的成员,该杆菌利用这些调节素来破坏宿主的固有免疫反应。白细胞介素-12(IL-12)的产生对于宿主针对结核分枝杆菌产生有效的免疫反应至关重要。我们证明,Man-LAM抑制脂多糖(LPS)后续刺激介导的IL-12 p40产生。Man-LAM以不依赖IL-10的方式抑制LPS诱导的IL-12 p40表达。它减弱LPS诱导的NF-κB驱动的荧光素酶基因表达,表明其作用可能与抑制NF-κB直接相关。这可能是由于Toll样受体信号传导的减弱。Man-LAM抑制IL-1受体相关激酶(IRAK)-TRAF6相互作用以及IκB-α磷酸化。它直接减弱c-Rel和p50的核转位和DNA结合。Man-LAM通过诱导TLR信号的负调节因子Irak-M的表达来发挥这些作用。通过RNA干扰敲低Irak-M表达可恢复在经Man-LAM预处理的细胞中LPS诱导的IL-12产生。Irak-M表达可由酵母甘露聚糖引发这一事实表明,LAM的甘露寡糖帽与甘露糖受体的结合可能是诱导IRAK-M的触发因素。

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