Stat6-Dependent Inhibition of Mincle Expression in Mouse and Human Antigen-Presenting Cells by the Th2 Cytokine IL-4.
Stat6-Dependent Inhibition of Mincle Expression in Mouse and Human Antigen-Presenting Cells by the Th2 Cytokine IL-4.
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DOI：
10.3389/fimmu.2016.00423
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发表时间：
2016
影响因子：
7.3
通讯作者：
Lang R
中科院分区：
文献类型：
--
作者：
Hupfer T;Schick J;Jozefowski K;Voehringer D;Ostrop J;Lang R
C型凝集素受体(CLRs)Mincle、Mc1和Dectin-2与分枝杆菌和真菌的细胞壁糖脂和碳水化合物结合。最近，我们描述了在GM-CSF和IL-4的存在下，这些CLR的表达在人单核细胞向树突状细胞(DC)分化的过程中下调。在这里，我们证明了Th2细胞因子IL-4特异性地抑制人抗原提呈细胞(APC)中Mincle、Mc1和Dectin-2的表达。IL-4的这种抑制作用是跨物种观察到的，因为用IL-4处理的小鼠巨噬细胞和DC也下调了这些受体的表达。IL-4可阻断Mincle配体海藻糖-6，6-联苯乙酸酯(TDB)对小鼠巨噬细胞Mincle和Mcl基因表达及细胞表面蛋白的上调作用，而TLR4配体则可对抗IL-4的抑制作用。在功能上，IL-4下调Mincle的表达伴随着TDB刺激时细胞因子的产生减少。IL-4的这些抑制作用依赖于转录因子Stat6。综上所述，我们的结果表明，关键的Th2细胞因子IL-4对Mincle和其他Dectin-2簇CLR在小鼠和人类巨噬细胞和DC中的表达产生负面影响，这可能使这些哨兵细胞对分枝杆菌和真菌配体的感知降低。
The C-type lectin receptors (CLRs) Mincle, Mcl, and Dectin-2 bind mycobacterial and fungal cell wall glycolipids and carbohydrates. Recently, we described that expression of these CLR is downregulated during differentiation of human monocytes to dendritic cells (DC) in the presence of GM-CSF and IL-4. Here, we demonstrate that the Th2 cytokine IL-4 specifically inhibits expression of Mincle, Mcl, and Dectin-2 in human antigen-presenting cells (APC). This inhibitory effect of IL-4 was observed across species, as murine macrophages and DC treated with IL-4 also downregulated these receptors. IL-4 blocked upregulation of Mincle and Mcl mRNA expression and cell surface protein by murine macrophages in response to the Mincle ligand Trehalose-6,6-dibehenate (TDB), whereas the TLR4 ligand LPS overcame inhibition by IL-4. Functionally, downregulation of Mincle expression by IL-4 was accompanied by reduced cytokine production upon stimulation with TDB. These inhibitory effects of IL-4 were dependent on the transcription factor Stat6. Together, our results show that the key Th2 cytokine IL-4 exerts a negative effect on the expression of Mincle and other Dectin-2 cluster CLR in mouse and human macrophages and DC, which may render these sentinel cells less vigilant for sensing mycobacterial and fungal ligands.
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