Cytokines in stress response ; molecular basis as mediators for homeostasis

已有的经验表明，应激可导致疾病；然而，应激破坏宿主防御的途径尚不清楚，也没有客观评估应激反应的方法。在本研究中，我们研究了(1)白介素18(IL-18)应激诱导的分子基础，(2)实验性应激小鼠血浆细胞因子和趋化因子的水平，(3)IL-18在下丘脑-垂体-肾上腺轴应激激活中的作用，(4)建立了细胞因子的蛋白质芯片系统。结果表明：(1)急性束缚应激通过肾上腺皮质NADPH加氧酶激活Caspase-1，导致IL-18分泌到血液中；(2)束缚或隔离小鼠血浆中细胞因子和趋化因子水平不同，表明细胞因子不是一般适应综合征的情况；(3)IL-18参与应激后下丘脑-垂体-肾上腺轴的激活，介导了Feedba…。更多的CK环用于持续激活下丘脑-垂体-肾上腺轴；(4)从少量血浆样本中重复性和准确地测定细胞因子。这些阐明表明，IL-18是免疫、内分泌和神经系统的连接分子，在宿主防御的动态平衡反应中起着关键作用，严重的应激导致IL-18系统的过度激活，从而可能导致宿主防御网络的破坏。此外，血浆中细胞因子和趋化因子浓度可能是应激源持续时间、严重程度、背景和风险的生物标志物。结合应激通过下丘脑-垂体-肾上腺轴导致心理和精神异常的研究结果，我们的发现表明，研究应激反应中的细胞因子可能为应激相关疾病提供一种可能的治疗手段，如抑郁症、FTSD、精神分裂症、自身免疫性疾病、代谢综合征和心肌病。基于这些发现，已经开始了一项研究，以澄清与压力相关的细胞因子诱导级联反应的分子基础。较少

It has been empirically known that stress induces disorders; however, the pathway by which stress disrupts host defense was not clarified and there was no means to objectively assess stress response. In this research project, we investigated (1) molecular basis for stress-induction of interleukin (IL) -18, (2) plasma levels of cytokines and chemokines in mice exposed to experimental stress, and (3) a role of IL-18 in stress-activation on hypothalamic-pituitary-adrenal axis, and (4) established a protein-array system for cytokines determination. Here we showed that (1) acute immobilization stress activates caspase-1 via NADPH oxydase in the adrenal cortex to cause IL-18 secretion into blood, (2) distinct plasma levels of cytokines and chemokines are formed in mice exposed to immobilization or isolation, demonstrating that cytokines are not a case of general adaptation syndrome, (3) IL-18 is involved in an activation of hypothalamic-pituitary-adrenal axis after stress, mediating a feedba … More ck loop for sustained activation of hypothalamic-pituitary-adrenal axis, and (4) reproducible and accurate determination for cytokines from a few amount of plasma samples. These elucidations indicate that IL-18 is a connecting molecule for immue, endocrine, and neural systems, playing a pivotal role in homeostatic response of host defense, and that severe stress causes hyper-activation of the IL-18 system, which may lead to a disrupted network for host defenses. Further, cytokines and chemokines concentrations in plasma are suggested to be a possible biomarkers for duration, severity, context, and risk of stressors. Together with the findings that stress induces psychological and psychiatric abnormalities via hypothalamic-pituitary-adrenal axis, our finding suggest that investigation on cytokines in stress response may provide a possible therapeutic means for stress-related diseases, such as depression, FTSD, schizophrenia, autoimmune diseases, metabolic syndromes, and cardiomyopathy. Based on the findings, a study to clarify a molecular basis for stress-related cytokines inducing cascade has been started. Less