Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, China; The Key Laboratory of Major Autoimmune Diseases, 81 Meishan Road, Hefei, Anhui, China.
Department of Rheumatology, Anhui Provincial Hospital, Hefei, Anhui, China.
Cytokine Growth Factor Rev. 2019 Aug;48:1-10. doi: 10.1016/j.cytogfr.2019.07.002. Epub 2019 Jul 16.
Autoimmune diseases are a broad spectrum of disorders involved in the imbalance of T-cell subsets, in which interplay or interaction of Th1, Th17 and Tregs are most important, resulting in prolonged inflammation and subsequent tissue damage. Pathogenic Th1 and Th17 cells can secrete signature proinflammatory cytokines, including interferon (IFN)-γ and IL-17, however Tregs can suppress effector cells and dampen a wide spectrum of immune responses. Melatonin (MLT) can regulate the humoral and cellular immune responses, as well as cell proliferation and immune mediators. Treatment with MLT directly interferes with T cell differentiation, controls the balance between pathogenic and regulatory T cells and regulates inflammatory cytokine release. MLT can promote the differentiation of type 1 regulatory T cells via extracellular signal regulated kinase 1/2 (Erk1/2) and retinoic acid-related orphan receptor-α (ROR-α) and suppress the differentiation of Th17 cells via the inhibition of ROR-γt and ROR-α expression through NFIL3. Moreover, MLT inhibits NF-κB signaling pathway to reduce TNF-α and IL-1β expression, promotes Nrf2 gene and protein expression to reduce oxidative and inflammatory states and regulates Bax and Bcl-2 to reduce apoptosis; all of which alleviate the development of autoimmune diseases. Thus, MLT can serve as a potential new therapeutic target, creating opportunities for the treatment of autoimmune diseases. This review aims to highlight recent advances in the role of MLT in several autoimmune diseases with particular focus given to novel signaling pathways involved in Th17 and Tregs as well as cell proliferation and apoptosis.
自身免疫性疾病是一组涉及 T 细胞亚群失衡的疾病，其中 Th1、Th17 和 Treg 的相互作用或相互影响最为重要，导致长期炎症和随后的组织损伤。致病性 Th1 和 Th17 细胞可以分泌特征性促炎细胞因子，包括干扰素（IFN）-γ和 IL-17，而 Treg 可以抑制效应细胞并抑制广泛的免疫反应。褪黑素（MLT）可以调节体液和细胞免疫反应以及细胞增殖和免疫介质。MLT 的治疗直接干扰 T 细胞分化，控制致病性和调节性 T 细胞之间的平衡，并调节炎症细胞因子的释放。MLT 可以通过细胞外信号调节激酶 1/2（Erk1/2）和维甲酸相关孤儿受体-α（ROR-α）促进 1 型调节性 T 细胞的分化，并通过抑制 ROR-γt 和 ROR-α 的表达来抑制 Th17 细胞的分化通过 NFIL3。此外，MLT 抑制 NF-κB 信号通路以减少 TNF-α 和 IL-1β 的表达，促进 Nrf2 基因和蛋白的表达以减少氧化和炎症状态，并调节 Bax 和 Bcl-2 以减少细胞凋亡；所有这些都减轻了自身免疫性疾病的发展。因此，MLT 可以作为一种潜在的新治疗靶点，为治疗自身免疫性疾病创造机会。本综述旨在强调 MLT 在几种自身免疫性疾病中的作用的最新进展，特别关注涉及 Th17 和 Treg 以及细胞增殖和凋亡的新信号通路。
