The roles of IFN-γ versus IL-17 in pathogenic effects of human Th17 cells on synovial fibroblasts
The roles of IFN-γ versus IL-17 in pathogenic effects of human Th17 cells on synovial fibroblasts
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DOI：
10.3109/s10165-012-0811-x
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发表时间：
2013-11-01
影响因子：
2.2
通讯作者：
Fox, David A.
中科院分区：
文献类型：
--
作者：
Kato, Hiroshi;Endres, Judith;Fox, David A.
目的 Th17 细胞虽然在宿主防御中不可或缺，但可能在许多自身免疫性疾病中发挥致病作用，包括类风湿性关节炎 (RA)。然而，人类 Th17 细胞驱动自身免疫的机制尚未完全明确。我们评估了人 Th17 CD4 T 细胞亚群通过成纤维样滑膜细胞 (FLS) 诱导细胞间相互作用分子和炎症介质表达的潜力，以及 IFN-γ 和 IL-17 在这些相互作用中的作用。方法 Th1 或 Th17 细胞从健康成人供体 CD4 T 细胞中诱导，并与 FLS 共培养 48 小时，有/没有中和 IFN-γ、IL-17A、或两者兼而有之。或者，仅用 IFN-γ 或 IL-17 处理 FLS 48 小时。分别通过表面染色、流式细胞术和 ELISA 评估 FLS 的 CD40、CD54 和 MHC-II 表达以及 IL-6 和 IL-8 分泌。 结果 Th1 和 Th17 细胞均分泌 IL-17 以及 IFN-γ，尽管 Th1 细胞产生的 IFN-γ 要高得多。与 Th1 细胞共培养后，CD40、CD54 和 MHC-II 的 FLS 表达显着增加，而 Th17 细胞仅增加 CD54+ 的 FLS 百分比。两种 T 细胞亚群均诱导 RA FLS 分泌 IL-6 和 IL-8。 IL-17A 的中和不会降低 CD40、MHC-II 或 CD54 的 FLS 表达，但会抑制 IL-6 和 IL-8 的分泌。虽然 IFN-gamma 是 IL-6 分泌的弱诱导剂，并且当用作单一刺激时显着抑制 FLS 的 IL-8 分泌，但 IFN-gamma 的中和抑制了 Th17/FLS 与 RA 共培养物中两种细胞因子的分泌，但不抑制 OA FLS。结论 FLS 细胞间相互作用分子和可溶性炎症介质受 IFN-gamma 和 IL-17 的差异调节。 IFN-γ的作用可能部分取决于其他共存细胞因子的特定环境及其诱导细胞间相互作用的潜力。 IL-17 或 IFN-γ 治疗中和的潜在益处可能取决于 RA 患者滑膜室中这些细胞因子的相对比例。
Objectives Th17 cells, while indispensable in host defense, may play pathogenic roles in many autoimmune diseases, including rheumatoid arthritis (RA). However, the mechanisms by which human Th17 cells drive auto-immunity have not been fully defined. We assessed the potential of the human Th17 CD4 T cell subset to induce expression of cell-cell interaction molecules and inflammatory mediators by fibroblast-like synoviocytes (FLS), and the roles of IFN-gamma and IL-17 in these interactions.Methods Th1 or Th17 cells were induced from healthy adult donor CD4 T cells and were co-cultured with FLS for 48 h with/without neutralization of IFN-gamma, IL-17A, or both. Alternatively, FLS were treated only with IFN-gamma or IL-17 for 48 h. FLS expression of CD40, CD54, and MHC-II, as well as IL-6 and IL-8 secretion, were assessed by surface staining followed by flow cytometry and ELISA, respectively.Results Both Th1 and Th17 cells secreted IL-17 as well as IFN-gamma, although IFN-gamma production was much greater from Th1 cells. FLS expression of CD40, CD54, and MHC-II significantly increased upon co-culture with Th1 cells, while Th17 cells increased only the percentage of FLS that were CD54+. Both T cell subsets induced IL-6 and IL-8 secretion by RA FLS. Neutralization of IL-17A did not reduce FLS expression of CD40, MHC-II, or CD54, but did inhibit IL-6 and IL-8 secretion. Although IFN-gamma was a weak inducer of IL-6 secretion and significantly inhibited IL-8 secretion from FLS when used as a single stimulus, neutralization of IFN-gamma inhibited the secretion of both cytokines in Th17/FLS co-cultures with RA but not OA FLS.Conclusion FLS cell-cell interaction molecules and soluble inflammatory mediators are differentially regulated by IFN-gamma and IL-17. The effects of IFN-gamma may depend in part on the particular milieu of other co-existing cytokines and its potential to induce cell-cell interactions. The potential benefit of therapeutic neutralization of either IL-17 or IFN-gamma could depend on the relative proportions of these cytokines in the synovial compartment of an RA patient.