Inflammation Chimiokines et Immunopathologie, INSERM, Fac. de pharmacie-Univ. Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France; Laboratory of Toxicology, Faculty of Pharmacy, Saint-Joseph University, Beirut, Lebanon.
Laboratory of Toxicology, Faculty of Pharmacy, Saint-Joseph University, Beirut, Lebanon.
J Invest Dermatol. 2017 Oct;137(10):2140-2148. doi: 10.1016/j.jid.2017.05.025. Epub 2017 Jun 17.
Allergic contact dermatitis, caused by nickel, is a delayed-type hypersensitivity reaction, and 14.5% of the general population may be affected in Europe. Among a wide range of cytokines, the IL-12 family has unique structural and immunological characteristics. Whereas IL-12p70 promotes T helper (Th) 1 cell polarization, IL-23 promotes Th17 cell development and both have been isolated from nickel-allergic patients. In this work, we were interested in understanding the mechanism behind nickel-induced Th17 cell development. We showed that nickel induced an early production of IL-23 in human monocyte-derived dendritic cells along with an increase in the expression of il-23p19 and il-12p40 mRNA. However, the production of a significant level of IL-12p70 required an additional signal such as IFN-γ. Moreover, nickel-treated monocyte-derived dendritic cells induced an increase in the percentage of IL-17A CD4 T cells, an effect reduced by IL-23 neutralization. We then investigated the molecular mechanism of IL-23 production. Our results showed that toll-like receptor 4, p38 mitogen-activated protein kinase, and NF-κB were involved in IL-23 production induced by nickel. However, Jak-signal transducer and activator of transcription activation seems to maintain the IL-23/IL-12p70 balance by limiting IL-23 production and promoting Th1 polarization. These results indicate that nickel-induced Th17 cell development is dependent on the production of IL-23 by human monocyte-derived dendritic cells via toll-like receptor 4, p38 mitogen-activated protein kinase, NF-κB, and Jak-signal transducer and activator of transcription pathways.
镍所致的过敏性接触性皮炎是一种迟发型超敏反应，欧洲有 14.5%的普通人群可能受到影响。在广泛的细胞因子中，IL-12 家族具有独特的结构和免疫学特征。虽然 IL-12p70 促进辅助性 T 细胞（Th）1 细胞极化，IL-23 促进 Th17 细胞的发育，但两者都已从镍过敏患者中分离出来。在这项工作中，我们有兴趣了解镍诱导 Th17 细胞发育的机制。我们表明，镍诱导人单核细胞来源的树突状细胞早期产生 IL-23，同时增加 il-23p19 和 il-12p40 mRNA 的表达。然而，要产生大量的 IL-12p70，需要 IFN-γ等额外信号。此外，镍处理的单核细胞来源的树突状细胞诱导 IL-17A CD4 T 细胞的百分比增加，IL-23 中和可降低该效应。然后，我们研究了 IL-23 产生的分子机制。我们的结果表明，Toll 样受体 4、p38 丝裂原活化蛋白激酶和 NF-κB 参与镍诱导的 IL-23 产生。然而，Jak-信号转导和转录激活似乎通过限制 IL-23 的产生和促进 Th1 极化来维持 IL-23/IL-12p70 的平衡。这些结果表明，镍诱导的 Th17 细胞发育依赖于人单核细胞来源的树突状细胞通过 Toll 样受体 4、p38 丝裂原活化蛋白激酶、NF-κB 和 Jak-信号转导和转录激活途径产生的 IL-23。
