IL-4 abrogates TH17 cell-mediated inflammation by selective silencing of IL-23 in antigen-presenting cells
IL-4 abrogates TH17 cell-mediated inflammation by selective silencing of IL-23 in antigen-presenting cells
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DOI：
10.1073/pnas.1416922112
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发表时间：
2015-02-17
影响因子：
11.1
通讯作者：
Biedermann, Tilo a
中科院分区：
文献类型：
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作者：
Guenova, Emmanuella;Skabytska, Yuliya;Biedermann, Tilo a
白细胞介素4（IL-4）可以抑制迟发型超敏反应（DTHR），包括小鼠和人类的器官特异性自身免疫性疾病。尽管广泛记录了IL-4的抗肿瘤作用，但其潜在的作用模式仍不完全清楚，因为IL-4还在体内促进树突状细胞（DC）和产生IFN-γ的T（H）1细胞产生IL-12。研究IL-4对人和小鼠DC极化的影响，我们发现IL-4对IL-12或IL-23的产生相反的作用。在促进DC产生IL-12的能力的同时，IL-4完全消除IL-23。骨髓嵌合体证明IL-4介导的DTHR抑制依赖于抗原呈递细胞中IL-23的信号转导和转录激活因子6（STAT6）依赖性消除。此外，尽管IL-12/T（H）1应答同时增强，但IL-4治疗通过STAT 6和转录激活因子3（ATF 3）依赖性抑制IL-23/T（H）17应答来减弱DTHR。由于IL-4疗法还改善人类银屑病并抑制IL-23/T（H）17应答而不阻断IL-12/T（H）1，因此选择性IL-4介导的IL-23/T（H）17沉默有望作为针对有害炎症的治疗，同时保留IL-12依赖性T（H）1应答。
Interleukin 4 (IL-4) can suppress delayed-type hypersensitivity reactions (DTHRs), including organ-specific autoimmune diseases in mice and humans. Despite the broadly documented antiinflammatory effect of IL-4, the underlying mode of action remains incompletely understood, as IL-4 also promotes IL-12 production by dendritic cells (DCs) and IFN-gamma-producing T(H)1 cells in vivo. Studying the impact of IL-4 on the polarization of human and mouse DCs, we found that IL-4 exerts opposing effects on the production of either IL-12 or IL-23. While promoting IL-12-producing capacity of DCs, IL-4 completely abrogates IL-23. Bone marrow chimeras proved that IL-4-mediated suppression of DTHRs relies on the signal transducer and activator of transcription 6 (STAT6)-dependent abrogation of IL-23 in antigen-presenting cells. Moreover, IL-4 therapy attenuated DTHRs by STAT6-and activating transcription factor 3 (ATF3)-dependent suppression of the IL-23/T(H)17 responses despite simultaneous enhancement of IL-12/T(H)1 responses. As IL-4 therapy also improves psoriasis in humans and suppresses IL-23/ T(H)17 responses without blocking IL-12/T(H)1, selective IL-4-mediated IL-23/T(H)17 silencing is promising as treatment against harmful inflammation, while sparing the IL-12-dependent T(H)1 responses.