Toll-like receptor and IL-12 signaling control susceptibility to contact hypersensitivity.
Toll-like receptor and IL-12 signaling control susceptibility to contact hypersensitivity.
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DOI：
10.1084/jem.20070509
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发表时间：
2008-09-01
影响因子：
15.3
通讯作者：
Freudenberg, Marina A.
中科院分区：
文献类型：
--
作者：
Martin, Stefan F.;Dudda, Jan C.;Bachtanian, Eva;Lembo, Annalisa;Liller, Stefanie;Duerr, Christoph;Heimesaat, Markus M.;Bereswill, Stefan;Fejer, Gyoergy;Vassileva, Ralitsa;Jakob, Thilo;Freudenberg, Nikolaus;Termeer, Christian C.;Johner, Caroline;Galanos, Chris;Freudenberg, Marina A.
变应性接触性超敏反应（CHS）是一种T细胞介导的炎症性皮肤病。白细胞介素（IL）-12被认为在变应原特异性T细胞应答的产生中是重要的。然而，IL-12 R β2缺陷小鼠中IL-12功能的丧失并不能改善过敏性免疫应答，提示在CHS的诱导中存在替代的IL-12非依赖性途径。由于接触过敏原总是发生在微生物皮肤植物群的存在下，我们研究了Toll样受体（TLR）在诱导CHS中的潜在作用。使用缺乏TLR 4、细菌脂多糖（LPS）受体、IL-12受体（R）β2或两者的小鼠，我们表明，同时缺乏TLR 4和IL-12 R β2，而不是单独缺乏TLR 4或IL-12 R β2，阻止了DC介导的致敏、效应T细胞的产生，以及随后对2，4，6-三硝基-1-氯苯（TNCB）、恶唑酮、和异硫氰酸荧光素。将TLR 4转基因导入TLR 4/IL-12 R β2突变体恢复了CHS诱导，表明IL-12非依赖性CHS诱导需要TLR 4。此外，TLR 2和TLR 4的伴随缺乏阻止了IL-12感受态小鼠中CHS向TNCB的诱导。最后，CHS在无菌野生型和IL-12 R β2缺陷型小鼠中是可诱导的，但在无菌TLR 4/IL-12 R β2双缺陷型小鼠中不是，这表明必要的TLR激活可能通过内源性配体进行。
Allergic contact hypersensitivity (CHS) is a T cell–mediated inflammatory skin disease. Interleukin (IL)-12 is considered to be important in the generation of the allergen-specific T cell response. Loss of IL-12 function in IL-12Rβ2–deficient mice, however, did not ameliorate the allergic immune response, suggesting alternate IL-12–independent pathways in the induction of CHS. Because exposure to contact allergens always takes place in the presence of microbial skin flora, we investigated the potential role of Toll-like receptors (TLRs) in the induction of CHS. Using mice deficient in TLR4, the receptor for bacterial lipopolysaccharide (LPS), IL-12 receptor (R) β2, or both, we show that the concomitant absence of TLR4 and IL-12Rβ2, but not the absence of TLR4 or IL-12Rβ2 alone, prevented DC-mediated sensitization, generation of effector T cells, and the subsequent CHS response to 2,4,6-trinitro-1-chlorobenzene (TNCB), oxazolone, and fluorescein isothiocyanate. Introduction of the TLR4 transgene into the TLR4/IL-12Rβ2 mutant restored the CHS inducibility, showing a requirement for TLR4 in IL-12–independent CHS induction. Furthermore, the concomitant absence of TLR2 and TLR4 prevented the induction of CHS to TNCB in IL-12–competent mice. Finally, CHS was inducible in germ-free wild-type and IL-12Rβ2–deficient mice, but not in germ-free TLR4/IL-12Rβ2 double deficient mice, suggesting that the necessary TLR activation may proceed via endogenous ligands.
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影响因子：
5.4
作者：
Dudda, JC;Lembo, A;Martin, SF
通讯作者：
Martin, SF
影响因子：
5.4
作者：
Ehl, S;Bischoff, R;Freudenberg, M
通讯作者：
Freudenberg, M
影响因子：
4.4
作者：
Arrighi, JF;Rebsamen, M;Hauser, C
通讯作者：
Hauser, C
影响因子：
20.3
作者：
Buelens, C;Bartholomé, EJ;Goldman, M
通讯作者：
Goldman, M
影响因子：
6.1
作者：
Dearman, RJ;Humphreys, N;Kimber, I
通讯作者：
Kimber, I