Th2 cytokines down-regulate TLR expression and function in human intestinal epithelial cells
Th2 cytokines down-regulate TLR expression and function in human intestinal epithelial cells
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DOI：
10.4049/jimmunol.176.10.5805
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发表时间：
2006-05-15
影响因子：
4.4
通讯作者：
Podolsky, Daniel K.
中科院分区：
文献类型：
--
作者：
Mueller, Tobias;Terada, Tomohiro;Podolsky, Daniel K.
TLR在人肠上皮细胞（IEC）中发挥重要的免疫和非免疫功能。促炎性Th 1细胞因子已被证明可促进IEC中TLR的表达和功能，但关键Th 2细胞因子（IL-4、IL-5、IL-13）对IEC中TLR信号传导的作用迄今尚未阐明。我们用Th 2细胞因子刺激人模型IEC，并通过北方印迹、RT-PCR、实时RT-PCR、Western印迹和流式细胞术检测TLR mRNA和蛋白的表达。通过I-κ Ba磷酸化测定、用TLR配体刺激后的IL-8分泌的ELISA和LPS摄取的流式细胞术来确定TLR功能。IL-4和IL-13显著降低TLR 3和TLR 4 mRNA和蛋白表达，包括必需的TLR 4辅助受体MD-2。TLR 4/MD-2介导的LPS摄取和TLR配体诱导的I-κ B α磷酸化和IL-8分泌在Th 2型白细胞介素致敏的IEC中显著减少。Th 2细胞因子对IEC中TLR表达和功能的下调作用也抵消了标志性Th 1细胞因子IFN-γ刺激诱导的TLR信号传导增强。总之，Th 2细胞因子似乎抑制TLR在静息和Thl细胞因子致敏的人IEC中的表达和功能。在Th 2细胞因子的影响下，IEC中TLR功能减弱可能保护宿主免受过度TLR信号传导的影响，但也可能损害宿主肠道先天免疫防御，并增加IEC对慢性炎症的易感性以响应肠道微环境。总之，我们的数据强调了Th 2细胞因子在平衡人类IEC中TLR信号传导中的重要作用。
TLRs serve important immune and nonimmune functions in human intestinal epithelial cells (IECs). Proinflammatory Th1 cytokines have been shown to promote TLR expression and function in IECs, but the effect of key Th2 cytokines (IL-4, IL-5, IL-13) on TLR signaling in IECs has not been elucidated so far. We stimulated human model IECs with Th2 cytokines and examined TLR mRNA and protein expression by Northern blotting, RT-PCR, real-time RT-PCR, Western blotting, and flow cytometry. TLR function was determined by I-kappa Ba phosphorylation assays, ELISA for IL-8 secretion after stimulation with TLR ligands and flow cytometry for LPS uptake. IL-4 and IL-13 significantly decreased TLR3 and TLR4 mRNA and protein expression including the requisite TLR4 coreceptor MD-2. TLR4/MD-2-mediated LPS uptake and TLR ligand-induced I-kappa B alpha phosphorylation and IL-8 secretion were significantly diminished in Th2 cytokine-primed IECs. The down-regulatory effect of Th2 cytokines on TLR expression and function in IECs also counteracted enhanced TLR signaling induced by stimulation with the hallmark Thl cytokine IFN-gamma. In summary, Th2 cytokines appear to dampen TLR expression and function in resting and Thl cytokine-primed human IECs. Diminished TLR function in IECs under the influence of Th2 cytokines may protect the host from excessive TLR signaling, but likely also impairs the host intestinal innate immune defense and increases IEC susceptibility to chronic inflammation in response to the intestinal microenvironment. Taken together, our data underscore the important role of Th2 cytokines in balancing TLR signaling in human IECs.