TLR2 signaling depletes IRAK1 and inhibits induction of type I IFN by TLR7/9.
TLR2 signaling depletes IRAK1 and inhibits induction of type I IFN by TLR7/9.
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DOI：
10.4049/jimmunol.1102181
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发表时间：
2012-02-01
期刊：
影响因子：
--
通讯作者：
Harding CV
中科院分区：
文献类型：
--
作者：
Liu YC;Simmons DP;Li X;Abbott DW;Boom WH;Harding CV
病原体可以通过多种TLR发出信号，对细胞因子（包括I型IFN（IFN-I））的诱导具有协同或拮抗作用。IFN-I通常由TLR 9而不是TLR 2诱导。此外，我们先前报道了结核分枝杆菌或其他TLR 2激动剂的TLR 2信号传导抑制TLR 9诱导IFN-I和IFN-I依赖的MHC-I Ag交叉加工。目前的研究表明，脂肽诱导的TLR 2信号转导抑制TLR 9对IFN-α和IFN-β第一波mRNA的诱导，而对IFN-Ⅰ第二波mRNA的诱导不受抑制。TLR 2还抑制另一种MyD 88依赖性IFN-I诱导受体TLR 7对IFN-I的诱导，但不抑制TLR 3或TLR 4（均为TRIF依赖性，MyD 88非依赖性）对IFN-I的诱导。TLR 2的抑制作用不依赖于新的蛋白质合成或细胞间信号传导。IRAK 1被TLR 2激动剂快速（10分钟内）耗尽，但直到后来（例如2小时）才被TLR 9激动剂耗尽。由于IRAK 1是TLR 7/9诱导的IFN-I产生所必需的，我们提出TLR 2信号传导诱导IRAK 1的快速消耗，这削弱了TLR 7/9对IFN-I的诱导。TLR 2抑制TLR 7/9诱导IFN-I的这种新机制可能会影响对表达TLR 2和TLR 7/TLR 9配体的微生物的免疫应答，或对细菌/病毒共感染的应答。
Pathogens may signal through multiple TLRs with synergistic or antagonistic effects on the induction of cytokines, including type I IFN (IFN-I). IFN-I is typically induced by TLR9 but not TLR2. Moreover, we previously reported that TLR2 signaling by Mycobacterium tuberculosis or other TLR2 agonists inhibited TLR9 induction of IFN-I and IFN-I-dependent MHC-I Ag cross processing. The current studies revealed that lipopeptide-induced TLR2 signaling inhibited induction of first-wave IFN-α and IFN-β mRNA by TLR9, whereas induction of second wave IFN-I mRNA was not inhibited. TLR2 also inhibited induction of IFN-I by TLR7, another MyD88-dependent IFN-I-inducing receptor, but did not inhibit IFN-I induction by TLR3 or TLR4 (both TRIF-dependent, MyD88-independent). The inhibitory effect of TLR2 was not dependent on new protein synthesis or intercellular signaling. IRAK1 was depleted rapidly (within 10 min) by TLR2 agonist but not until later (e.g. 2 h) by TLR9 agonist. Since IRAK1 is required for TLR7/9 induced IFN-I production, we propose that TLR2 signaling induces rapid depletion of IRAK1, which impairs IFN-I induction by TLR7/9. This novel mechanism, whereby TLR2 inhibits IFN-I induction by TLR7/9, may shape immune responses to microbes that express ligands for both TLR2 and TLR7/TLR9, or responses to bacteria/virus co-infection.
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