Shandong Provincial Qianfoshan Hospital, Shandong University, Jingshi Road 16766, Jinan, 250014, Shandong, People's Republic of China.
Medical Research Center of The Affiliated Hospital of Qingdao University, Wutaishan Road 1677, Qingdao, 266000, Shandong, People's Republic of China.
Arthritis Res Ther. 2019 Oct 28;21(1):220. doi: 10.1186/s13075-019-2001-0.
CD38+ NK cells are overabundant in rheumatoid arthritis (RA). Cyanidin-3-O-glucoside (C3G) is an inhibitor of CD38. This study investigated the pathogenic role of CD38+ NK cells and the effect of C3G on RA.
Rats with bovine type II collagen-induced arthritis (CIA) were injected with C3G. RA synovial fibroblasts (RASFs) or mononuclear cells (MNCs) were cultured with C3G. MNCs were also cocultured with CD38+ NK cells following C3G pretreatment.
C3G injection significantly alleviated CIA. C3G also significantly increased the level of interleukin (IL)-10 and the regulatory T (Treg) cell proportion, and it decreased the interleukin (IL)-6 and interferon (IFN)-γ levels and CD38+ NK cell proportion in rat peripheral blood and synovial fluid. Additionally, C3G significantly increased RASF apoptosis and decreased RASF proliferation and IL-6 production in the culture medium. Furthermore, C3G stimulated MNCs to increase IL-2 and IL-10 production and the Treg cell proportion, and it caused MNCs to decrease IL-6 and IFN-γ production and the CD38+ NK cell proportion. Although CD38+ NK cells significantly decreased the Treg cell proportion and IL-10 level in MNCs, CD38+ NK cells that had been pretreated with C3G increased the proportion of Treg cells and IL-10 levels and decreased the IL-6 and IFN-γ levels in the coculture. In CD38+ NK cells, C3G significantly increased Sirtuin 6 (Sirt6) expression and the tumor necrosis factor (TNF)-α level, and it decreased natural killer group 2D (NKG2D) expression and the IFN-γ level. However, when CD38+ NK cells were treated with Sirt6 siRNA, C3G did not change the NKG2D expression, the TNF-α level sharply decreased, and the IFN-γ level increased. When MNCs were cocultured with C3G-pretreated CD38+ NK cells in the presence of TNF-α and an anti-IFN-γ antibody, the IL-10+ Treg cell proportion significantly increased. When MNCs were cocultured with C3G-pretreated CD38+ NK cells in the presence of IFN-γ and an anti-TNF-α antibody, the IL-10+ Treg cell proportion sharply decreased. When CIA rats were injected with both C3G and the Sirt6 inhibitor OSS_128167, the rats exhibited joint inflammation and a low Treg cell proportion, but the CD38+ NK proportion was still low.
C3G has therapeutic effects on CIA and RA. C3G decreased the proportion of CD38+ cells, RASF proliferation, and proinflammatory cytokine secretion, and it increased the Treg cell proportion. C3G also elevated Sirt6 expression to suppress NKG2D expression, increase TNF-α secretion, and decrease IFN-γ secretion in CD38+ NK cells, which stimulates MNCs to differentiate into Treg cells. This study also demonstrates that the inhibition of Treg cell differentiation in MNCs by CD38+ NK cells is a potential cause of the immune imbalance in RA and CIA.
CD38+NK 细胞在类风湿关节炎（RA）中过度表达。矢车菊素-3-O-葡萄糖苷（C3G）是 CD38 的抑制剂。本研究探讨了 CD38+NK 细胞在 RA 发病机制中的作用及 C3G 对 RA 的作用。
牛Ⅱ型胶原诱导的关节炎（CIA）大鼠注射 C3G。用 C3G 培养 RA 滑膜成纤维细胞（RASFs）或单核细胞（MNCs）。用 C3G 预处理 CD38+NK 细胞后，将 MNC 进行共培养。
C3G 注射显著缓解 CIA。C3G 还显著增加了白细胞介素（IL）-10 和调节性 T（Treg）细胞比例，降低了大鼠外周血和滑膜液中白细胞介素（IL）-6 和干扰素（IFN）-γ水平和 CD38+NK 细胞比例。此外，C3G 显著增加 RASF 凋亡，降低 RASF 增殖和细胞培养液中 IL-6 产生。此外，C3G 刺激 MNC 增加白细胞介素（IL）-2 和白细胞介素（IL）-10 产生和 Treg 细胞比例，并降低 MNC 中白细胞介素（IL）-6 和 IFN-γ 产生和 CD38+NK 细胞比例。虽然 CD38+NK 细胞显著降低了 MNCs 中的 Treg 细胞比例和 IL-10 水平，但经 C3G 预处理的 CD38+NK 细胞增加了 Treg 细胞比例和 IL-10 水平，并降低了共培养物中的 IL-6 和 IFN-γ 水平。在 CD38+NK 细胞中，C3G 显著增加 Sirtuin 6（Sirt6）表达和肿瘤坏死因子（TNF）-α水平，降低自然杀伤组 2D（NKG2D）表达和 IFN-γ 水平。然而，当 CD38+NK 细胞用 Sirt6 siRNA 处理时，C3G 并未改变 NKG2D 表达，TNF-α 水平急剧下降，IFN-γ 水平升高。当 MNC 与用 TNF-α和抗 IFN-γ 抗体预处理的 C3G 预处理的 CD38+NK 细胞共培养时，IL-10+Treg 细胞比例显著增加。当 MNC 与用 IFN-γ 和抗 TNF-α 抗体预处理的 C3G 预处理的 CD38+NK 细胞共培养时，IL-10+Treg 细胞比例急剧下降。当 CIA 大鼠同时注射 C3G 和 Sirt6 抑制剂 OSS_128167 时，大鼠表现出关节炎症和 Treg 细胞比例降低，但 CD38+NK 细胞比例仍较低。
C3G 对 CIA 和 RA 具有治疗作用。C3G 降低了 CD38+细胞、RASF 增殖和促炎细胞因子的分泌，并增加了 Treg 细胞的比例。C3G 还通过抑制 CD38+NK 细胞中的 NKG2D 表达来提高 Sirt6 表达，增加 TNF-α 的分泌并降低 IFN-γ 的分泌，从而刺激 MNC 分化为 Treg 细胞。本研究还表明，CD38+NK 细胞对 MNC 中 Treg 细胞分化的抑制是 RA 和 CIA 免疫失衡的一个潜在原因。
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