Interleukin-29 induces epithelial production of CXCR3A ligands and T-cell infiltration
Interleukin-29 induces epithelial production of CXCR3A ligands and T-cell infiltration
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DOI：
10.1007/s00109-015-1367-y
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发表时间：
2016-04-01
影响因子：
4.7
通讯作者：
Wolk, Kerstin
中科院分区：
文献类型：
--
作者：
Witte, Ellen;Kokolakis, Georgios;Wolk, Kerstin
牛皮癣被认为是慢性免疫介导疾病的模型。 Th17 细胞是这些疾病的关键参与者。最近，我们证明 Th17 细胞产生白细胞介素 (IL)-29，并且 IL-29 在银屑病皮损中高度存在。 IL-29 对上皮细胞和黑素细胞的作用是否与银屑病发病机制有关，目前尚不清楚。对 IL-29 处理的人角质形成细胞的分析揭示了趋化因子 CXCL10、CXCL11 的诱导，以及较小程度的 CXCL9 的诱导。与已知可吸引 Th1-、CD8(+)、NK- 和 Th1/Th17 瞬时细胞的 CXCR3A 配体不同，未发现对吸引其他免疫细胞群的趋化因子或调节 CXCR3A/CXCR3A 配体相互作用的分子有影响。 IL-29 在黑素细胞、表皮模型和外植皮肤中也诱导了 CXCR3A 配体表达。至于其他与银屑病相关的细胞因子，干扰素 γ 以及效力较弱的肿瘤坏死因子 α 和 IL-1 β 共享并增强了 IL-29 的能力。将小鼠 IL-29 对应物注射到小鼠皮肤中会引发局部 CXCL10 和 CXCL11 表达、T 细胞浸润，从而导致皮肤肿胀。与这些患者的非病变皮肤以及缺乏 IL-29 产生的健康供体和特应性皮炎患者的皮肤相比，银屑病病变中 IL-29 表达升高与 CXCR3A 配体的上调相关。重要的是，IL-29 的中和降低了银屑病病变外植体培养物中 CXCR3A 配体的水平。最后，在银屑病中发现血液 CXCL11 水平升高，这可能有助于监测 IL-29 轴的病变活动。总之，Th17 细胞因子 IL-29 诱导特定的趋化因子，从而引发潜在致病性 T 细胞的皮肤浸润。
Psoriasis is considered as a model for chronic immune-mediated disorders. Th17-cells are pivotal players in those diseases. Recently, we demonstrated that Th17-cells produce interleukin (IL)-29 and that IL-29 is highly present in psoriatic lesions. Whether IL-29, with its action on epithelial cells and melanocytes, contributes to psoriasis pathogenesis, was unknown so far. Analysis of IL-29-treated human keratinocytes revealed induction of the chemokines CXCL10, CXCL11, and, to a much lesser extent, CXCL9. Unlike these CXCR3A ligands, known to attract Th1-, CD8(+), NK-, and Th1/Th17 transient cells, no influence was found on chemokines attracting other immune cell populations or on molecules modulating the CXCR3A/CXCR3A ligand interaction. CXCR3A ligand expression was also induced by IL-29 in melanocytes and in epidermis models and explanted skin. Regarding other psoriasis-relevant cytokines, interferon-gamma and, less potently, tumor necrosis factor-alpha and IL-1 beta shared and strengthened IL-29's capacity. Murine IL-29 counterpart injected into mouse skin provoked local CXCL10 and CXCL11 expression, T-cell infiltration, and, in consequence, skin swelling. The elevated IL-29 expression in psoriatic lesions was associated with upregulation of CXCR3A ligands compared to non-lesional skin of these patients and to the skin of healthy donors and atopic dermatitis patients, which lack IL-29 production. Importantly, neutralization of IL-29 reduced CXCR3A ligand levels in explant cultures of psoriatic lesions. Finally, elevated blood CXCL11 levels were found in psoriasis that might be useful for monitoring lesional activity of the IL-29 axis. In summary, the Th17-cytokine IL-29 induces specific chemokines and, in consequence, provokes skin infiltration of potentially pathogenic T-cells.