Interleukin-6 inhibits apoptosis of exocrine gland tissues under inflammatory conditions.
Interleukin-6 inhibits apoptosis of exocrine gland tissues under inflammatory conditions.
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DOI：
10.1016/j.cyto.2015.07.027
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发表时间：
2015-12
期刊：
影响因子：
3.8
通讯作者：
Yu Q
中科院分区：
文献类型：
--
作者：
Zhou J;Jin JO;Patel ES;Yu Q
白细胞介素（IL）-6是一种多功能细胞因子，可促进或抑制组织炎症，这取决于特定的疾病背景。IL-6在干燥综合征（SS）患者的外分泌腺和血清中升高，但IL-6在该病发病机制中的具体作用尚未确定。在这项研究中，我们发现，IL-6的表达水平随着年龄的增加，在C56 BL/6. NOD-Aec 1Aec 2小鼠，一个主要的SS模型，并高于对照C57 BL/6小鼠。为了评估IL-6在SS发展的免疫学阶段中的作用，将中和性抗IL-6抗体给予16周龄雌性C56 BL/6. NOD-Aec 1Aec 2小鼠，每周3次，连续8周。在SS发展的整个免疫阶段，内源性IL-6的中和导致唾液腺中细胞凋亡、caspase-3激活、白细胞浸润以及IFN-γ和TNF-α产生增加。为了进一步确定IL-6对外分泌腺细胞凋亡的影响，将重组人IL-6或中和性抗IL-6抗体注射到接受抗CD 3抗体同时注射的雌性C57 BL/6小鼠中以诱导外分泌腺细胞凋亡。在该模型中，IL-6的中和作用增强，而IL-6的给药抑制唾液腺和泪腺中的细胞凋亡和半胱天冬酶-3活化。IL-6的抑制前列腺增生作用与两种腺体中Bcl-xL和Mcl-1的上调有关。此外，IL-6处理诱导STAT 3的活化和上调Bcl-xL和Mcl-1基因在人唾液腺上皮细胞系中的表达。总之，IL-6抑制外分泌腺组织的凋亡，并在包括SS在内的炎症条件下发挥组织保护作用。这些发现提示了在自身免疫和炎症条件下利用IL-6的这种特性来保护外分泌腺组织完整性和功能的可能性。
Interleukin (IL)-6 is a multi-functional cytokine that can either promote or suppress tissue inflammation depending on the specific disease context. IL-6 is elevated in the exocrine glands and serum of patients with Sjögren’s syndrome (SS), but the specific role of IL-6 in the pathogenesis of this disease has not been defined. In this study, we showed that IL-6 expression levels were increased with age in C56BL/6.NOD-Aec1Aec2 mice, a primary SS model, and higher than the control C57BL/6 mice. To assess the role of IL-6 during the immunological phase of SS development, a neutralizing anti-IL-6 antibody was administered into 16 week-old female C56BL/6.NOD-Aec1Aec2 mice, 3 times weekly for a consecutive 8 weeks. Neutralization of endogenous IL-6 throughout the immunological phase of SS development led to increased apoptosis, caspase-3 activation, leukocytic infiltration, and IFN-γ- and TNF-α production in the salivary gland. To further determine the effect of IL-6 on the apoptosis of exocrine gland cells, recombinant human IL-6 or the neutralizing anti-IL-6 antibody was injected into female C57BL/6 mice that received concurrent injection of anti-CD3 antibody to induce the apoptosis of exocrine glands. Neutralization of IL-6 enhanced, whereas administration of IL-6 inhibited apoptosis and caspase-3 activation in salivary and lacrimal glands in this model. The apoptosis-suppressing effect of IL-6 was associated with up-regulation of Bcl-xL and Mcl-1 in both glands. Moreover, IL-6 treatment induced activation of STAT3 and up-regulated Bcl-xL and Mcl-1 gene expression in a human salivary gland epithelial cell line. In conclusion, IL-6 inhibits the apoptosis of exocrine gland tissues and exerts a tissue-protective effect under inflammatory conditions including SS. These findings suggest the possibility of using this property of IL-6 to preserve exocrine gland tissue integrity and function under autoimmune and inflammatory conditions.