IL-29 Is Produced by TH17 Cells and Mediates the Cutaneous Antiviral Competence in Psoriasis
IL-29 Is Produced by TH17 Cells and Mediates the Cutaneous Antiviral Competence in Psoriasis
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DOI：
10.1126/scitranslmed.3006245
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发表时间：
2013-09-25
影响因子：
17.1
通讯作者：
Sabat, Robert
中科院分区：
文献类型：
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作者：
Wolk, Kerstin;Witte, Katrin;Sabat, Robert
牛皮癣和特应性皮炎（AD）是最常见的慢性炎症性皮肤病。尽管两组患者的皮肤屏障功能均严重受损，但只有 AD 患者经常遭受皮肤病毒感染。对这些致病且常常危及生命的感染的不同易感性的机制尚不清楚。我们发现，与 AD 病变和健康皮肤相比，银屑病患者中的 MX1、BST2、ISG15 和 OAS2 等抗病毒蛋白 (AVP) 显着升高。在银屑病皮损中 30 种单独定量的细胞因子中，白细胞介素 29 (IL-29) 是唯一其表达与 AVP 水平相关的介质。 AD 皮损中不存在 IL-29，银屑病皮肤中 IL-29 的中和可降低 AVP 表达。因此，IL-29 提高了分离的角质形成细胞、表皮模型和人类皮肤外植体中的 AVP 水平，但不影响抗菌蛋白的产生。 AVP 诱导与 IL-29 处理的角质形成细胞的抗病毒防御能力增强相关。此外，IL-29 提高了信号元件的表达，导致角质形成细胞对其自身作用的敏感性增加。我们将辅助 T 17 (T(H)17) 细胞鉴定为 IL-29 产生者，并证明它们能够以 IL-29 依赖性方式提高角质形成细胞的抗病毒能力。转化生长因子-β 和 ROR gamma t/ROR α 的活性对于产生 IL-29 的 T(H)17 细胞的发育最为关键。这些细胞的 IL-29 分泌依赖于 NFAT 和 c-Jun N 末端激酶，并被 IL-4 抑制。这些数据表明，AD 中不存在的 T(H)17 细胞衍生的 IL-29 介导银屑病皮肤的强抗病毒状态，并证明了 T(H)17 细胞的新功能。
Psoriasis and atopic dermatitis (AD) are the most common chronic inflammatory skin diseases. Although both patient groups show strongly impaired skin barrier function, only AD patients frequently suffer from cutaneous viral infections. The mechanisms underlying the distinct susceptibilities to these pathogenetic and often life-threatening infections are unknown. We show that antiviral proteins (AVPs) such as MX1, BST2, ISG15, and OAS2 were strongly elevated in psoriatic compared to AD lesions and healthy skin. Of 30 individually quantified cytokines in psoriatic lesions, interleukin-29 (IL-29) was the only mediator whose expression correlated with the AVP levels. IL-29 was absent in AD lesions, and neutralization of IL-29 in psoriatic skin reduced AVP expression. Accordingly, IL-29 raised AVP levels in isolated keratinocytes, epidermis models, and human skin explants, but did not influence antibacterial protein production. AVP induction correlated with increased antiviral defense of IL-29-treated keratinocytes. Furthermore, IL-29 elevated the expression of signaling elements, resulting in increased sensitivity of keratinocytes toward its own action. We identified T helper 17 (T(H)17) cells as IL-29 producers and demonstrated their ability to increase the antiviral competence of keratinocytes in an IL-29-dependent manner. Transforming growth factor-beta and the activity of ROR gamma t/ROR alpha were most critical for the development of IL-29-producing T(H)17 cells. IL-29 secretion by these cells was dependent on NFAT and c-Jun N-terminal kinase and was inhibited by IL-4. These data suggest that T(H)17 cell-derived IL-29, which is absent in AD, mediates the robust antiviral state on psoriatic skin, and demonstrate a new function of T(H)17 cells.