Brain Behav.Immu.：发现细胞因子致抑郁症个体易感决定因素
抑郁症是危害人类健康的主要心理疾病之一，给患者的心理社会功能和生活质量带来严重影响。抑郁症的病因机制非常复杂，有多种假说，而目前较为前瞻和具有潜力的是细胞因子假说。但迄今细胞因子在抑郁症中扮演的确切角色并不清楚，其作用是直接的还是与其它因素相互作用的都不明确，这种状态已成为制约细胞因子假说进行深入研究的瓶颈。
中国科学院心理健康重点实验室林文娟研究员及其博士生王东林等研究者提出假设，认为糖皮质激素受体（glucocorticoid receptor，GR）功能状态可能是细胞因子所致抑郁症的个体易感性的决定因素。为探讨GR在炎性细胞因子所致抑郁行为中的作用，研究人员使用GR阻断剂分别以就急性单次、慢性反复等不同阻断方式，考察阻断GR功能对急性和慢性免疫激活所诱导的大鼠的抑郁行为和炎性细胞因子的时程变化。研究发现，在未阻断或未有效阻断GR的情况下，急性免疫激活引起显著但短暂的炎性细胞因子增多和抑郁样行为；而在有效阻断GR的情况下，无论急性或慢性免疫激活都引起显著而持久的炎性细胞因子增多和抑郁样行为。
这些结果表明，GR功能正常或轻微短暂障碍者不易受急性或慢性免疫激活的作用而形成持久的炎性细胞因子的过度分泌及抑郁，而GR功能异常者则容易受急性或慢性免疫激活的作用而形成持久的炎性细胞因子的激活及抑郁。
研究进一步发现，机体免疫炎性应答所诱发各种炎性细胞因子的分泌中，肿瘤坏死因子α（TNFα）和干扰素γ（IFNγ）的增高最为明显，而它们是激活色胺酸前体代谢酶吲哚胺2，3－二氧化酶（IDO）的关键因子。IDO过渡激活可导致5－羟色胺合成明显下降。这些发现与精神病学权威杂志Molecular Psychiatry发表的IDO的致抑郁作用吻合。
研究还发现，在GR功能异常的情况下，免疫激活所致抑郁行为的形成不仅与炎性细胞因子的变化有关，而且与HPA轴自身的功能变化有关。正常GR具有保护个体避免炎性细胞因子过度活动及相关抑郁症侵袭的重要功能，而异常GR则可能是炎性细胞因子过度活动及抑郁症形成的重要内在条件或参与因素。不同个体GR功能状态的差异可能决定着个体对细胞因子所致抑郁症的易感性的差异。
本研究提供的证据是对抑郁症细胞因子假说的重要补充，可为细胞因子导致抑郁症的病机理论增添新的解释。
该研究成果2011年在心理神经免疫学领域权威杂志�****************浴⑿形朊庖摺罚˙rain, Behavior, and Immunity）发表，国际同行认为该工作是有意义和创新性的发现。（生物谷Bioon.com）
生物谷推荐原文出处：
Brain, Behavior, and Immunity DOI： 10.1016/j.bbi.2011.01.011
Chronic blockade of glucocorticoid receptors by RU486 enhances lipopolysaccharide-induced depressive-like behaviour and cytokine production in rats
Donglin Wang, Wenjuan Lin , Yuqin Pan,, Xueying Kuang, Xiaoli Qi and Han Suna
Although accumulating evidence supports a role for cytokines in the pathophysiology of depression, the cytokine hypothesis of depression is debatable. It has been suggested that neuroendocrine and immune systems acting in concert may have roles in the development and the maintenance of the disease. Glucocorticoid receptor (GR) is the key element which exerts both anti-inflammatory and cytokine-inhibiting effects. Whether functional changes of GR are involved in the pathophysiology of cytokine-induced depression remains elusive. In the present study, the effects of both acute and chronic GR blockade on depressive-like behaviour and cytokine production induced by lipopolysaccharides (LPS), cytokine inducer, were investigated in rats. Acute or chronic blockade of GR was achieved by a single administration or repeated administrations, respectively, of the GR antagonist RU486 (RU). Behavioural measurements, including saccharin preference, locomotor activity, and immobility time, were assessed. The serum levels of proinflammatory cytokines (TNFα, IL-1β, and IFNγ) were determined by ELISA. The results showed that LPS induced significant but transient depressive-like behaviour. Repeated, but not single, administration of RU significantly enhanced and prolonged LPS-induced depressive-like behaviour and an increase in the serum production of TNFα and IFNγ. These results indicate that the effective blockade of GR enhanced the depressive-like behaviour induced by cytokines. Findings from this study suggest that GR dysfunction may be an important contributing factor to the development of cytokine-related depression. These findings add to the growing evidence of mechanis by which cytokines influence depression.
