Celastrol inhibits inflammatory stimuli-induced neutrophil extracellular trap formation.
Celastrol inhibits inflammatory stimuli-induced neutrophil extracellular trap formation.
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DOI：
10.2174/1566524015666150505160743
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发表时间：
2015
影响因子：
2.5
通讯作者：
Su K
中科院分区：
文献类型：
--
作者：
Yu Y;Koehn CD;Yue Y;Li S;Thiele GM;Hearth-Holmes MP;Mikuls TR;O'Dell JR;Klassen LW;Zhang Z;Su K
中性粒细胞胞外陷阱（NETs）是由活化的中性粒细胞释放的网状结构。最近的研究表明，NETs在类风湿关节炎（RA）和系统性红斑狼疮（SLE）等疾病的自身免疫和组织损伤中发挥积极作用。本研究的目的是研究雷公藤红素，一种三萜化合物，是否可以抑制与RA和SLE相关的炎症刺激诱导的NET形成。我们发现，celastrol可以完全抑制肿瘤坏死因子α (TNFα)诱导的中性粒细胞氧化破裂和NET形成，IC50为0.34µM，卵白蛋白：抗卵白蛋白免疫复合物（Ova IC）的IC50为1.53µM。雷公藤红素还能完全抑制从RA和SLE患者血清中纯化的免疫球蛋白G （IgG）诱导的中性粒细胞氧化破裂和NET形成。进一步研究其机制，我们发现celastrol处理下调了脾脏酪氨酸激酶（SYK）的激活，并随之下调了丝裂原活化蛋白激酶（MAPKK/MEK）、细胞外信号调节激酶（ERK）和nf - κ b抑制剂α (i - κ b α)的磷酸化，以及组蛋白的瓜氨酸化。我们的数据显示，celastrol可能通过下调SYK-MEK-ERK-NFκB信号级联，有效抑制不同炎症刺激诱导的中性粒细胞氧化破裂和NET形成。这些结果表明，celastrol可能具有治疗涉及中性粒细胞和NETs的炎症性和自身免疫性疾病的治疗潜力。
Neutrophil extracellular traps (NETs) are web-like structures released by activated neutrophils. Recent studies suggest that NETs play an active role in driving autoimmunity and tissue injury in diseases including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). The purpose of this study was to investigate if celastrol, a triterpenoid compound, can inhibit NET formation induced by inflammatory stimuli associated with RA and SLE. We found that celastrol can completely inhibit neutrophil oxidative burst and NET formation induced by tumor necrosis factor alpha (TNFα) with an IC50 of 0.34 µM and by ovalbumin:anti-ovalbumin immune complexes (Ova IC) with an IC50 of 1.53 µM. Celastrol also completely inhibited neutrophil oxidative burst and NET formation induced by immunoglobulin G (IgG) purified from RA and SLE patient sera. Further investigating into the mechanisms, we found that celastrol treatment downregulated the activation of spleen tyrosine kinase (SYK) and the concomitant phosphorylation of mitogen-activated protein kinase kinase (MAPKK/MEK), extracellular-signal-regulated kinase (ERK), and NFκB inhibitor alpha (IκBα), as well as citrullination of histones. Our data reveals that celastrol potently inhibits neutrophil oxidative burst and NET formation induced by different inflammatory stimuli, possibly through downregulating the SYK-MEK-ERK-NFκB signaling cascade. These results suggest that celastrol may have therapeutic potentials for the treatment of inflammatory and autoimmune diseases involving neutrophils and NETs.