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炎癥：與壓力有關(guān)的疾病的共同途徑 While modernization has dramatically increased lifespan, it has also witnessed that the nature of stress has changed dramatically. Chronic stress result failures of homeostasis thus lead to various diseases such as atherosclerosis, non-alcoholic fatty liver disease (NAFLD) and depression. However, while 75%–90% of human diseases is related to the activation of stress system, the common pathways between stress exposure and pathophysiological processes underlying disease is still debatable. Chronic inflammation is an essential component of chronic diseases. Additionally, accumulating evidence suggested that excessive inflammation plays critical roles in the pathophysiology of the stress-related diseases, yet the basis for this connection is not fully understood. Here we discuss the role of inflammation in stress-induced diseases and suggest a common pathway for stress-related diseases that is based on chronic mild inflammation. This framework highlights the fundamental impact of inflammation mechanisms and provides a new perspective on the prevention and treatment of stress-related diseases. 現(xiàn)代化在極大地延長(zhǎng)壽命的同時(shí),，也見(jiàn)證了壓力的本質(zhì)發(fā)生了巨大的變化。慢性壓力導(dǎo)致體內(nèi)平衡失調(diào),，從而導(dǎo)致各種疾病,，如動(dòng)脈粥樣硬化、非酒精性脂肪性肝病(NAFLD)和抑郁癥,。然而,，雖然75%-90%的人類疾病與壓力系統(tǒng)的激活有關(guān),，但應(yīng)激暴露與疾病病理生理過(guò)程的共同途徑仍存在爭(zhēng)議,。慢性炎癥是慢性疾病的重要組成部分,。此外,，越來(lái)越多的證據(jù)表明,，過(guò)度炎癥在壓力相關(guān)疾病的病理生理學(xué)中發(fā)揮著關(guān)鍵作用,，但這種聯(lián)系的基礎(chǔ)尚未完全破解,。在此，我們討論了炎癥在壓力性疾病中的作用,，并提出了一種基于慢性輕度炎癥的壓力相關(guān)疾病的共同途徑。這個(gè)框架強(qiáng)調(diào)了炎癥機(jī)制的基本影響,，并為壓力相關(guān)疾病的預(yù)防和治療提供了一個(gè)新的視角。 壓力是一種由心理、環(huán)境或生理壓力源引起的內(nèi)穩(wěn)態(tài)受到威脅的狀態(tài),。隨著科學(xué)技術(shù)的快速發(fā)展,，以及經(jīng)濟(jì)和社會(huì)競(jìng)爭(zhēng)的激烈，壓力的性質(zhì)發(fā)生了巨大的變化(Landsbergis, 2003),。壓力事件主要通過(guò)激活交感神經(jīng)系統(tǒng)(SNS)和下丘腦-垂體-腎上腺(HPA)軸，產(chǎn)生多種神經(jīng)化學(xué),、神經(jīng)遞質(zhì)和激素改變。當(dāng)壓力刺激受到控制時(shí),，身體會(huì)以生理方式對(duì)其做出反應(yīng)。SNA和HPA軸被喚醒,，釋放化學(xué)介質(zhì)來(lái)保護(hù)我們的身體免受壓力,。例如，兒茶酚胺升高會(huì)增加心率和血壓,，這有助于我們戰(zhàn)斗或逃跑。這種適當(dāng)?shù)纳眢w反應(yīng)被Sterling和yer(1988)稱為“異穩(wěn)態(tài)”。 這種狀態(tài)有利于我們的生存和恢復(fù),。然而，當(dāng)壓力刺激被延長(zhǎng)或過(guò)度夸大時(shí),，換句話說(shuō)，長(zhǎng)期增加的異穩(wěn)態(tài)導(dǎo)致病理生理。在過(guò)去二十年中,，不斷積累的證據(jù)表明,，嚴(yán)重或長(zhǎng)期（慢性）壓力導(dǎo)致身體和精神障礙的風(fēng)險(xiǎn)增加，這被稱為與壓力有關(guān)的疾病,。壓力是75%-90%疾病的共同危險(xiǎn)因素,，包括導(dǎo)致發(fā)病率和死亡率最高的疾病。根據(jù)之前的回顧,，最常見(jiàn)的與壓力相關(guān)的疾病是心血管疾病(CVD，即高血壓和動(dòng)脈粥樣硬化),、代謝性疾病(即糖尿病和非酒精性脂肪性肝病,，NAFLD)、精神疾病和神經(jīng)退行性疾病(即抑郁癥,、阿爾茨海默病、AD和帕金森病,，PD),、癌癥(Cohen et al.， 2007),。 The traditional standpoint of mechanisms linking stress and disease has focused on the classical stress systems—the HPA axis and SNS. However, alterations in HPA axis and SNS mainly have indirect effects on target systems; thus the mechanisms link stress to stress-related diseases, and are still under debate. Recently, inflammation as a new and promising biological mechanism is proposed (Rohleder, 2014). Accumulating literatures showed that excessive inflammation directly contribute to pathophysiology of stress-related diseases. In this review article, the search terms were combinations of the following (literatures were selected from PubMed): stress (“social stress” or “psychosocial stress” or “psychophysiological stress” or “mental stress”), disease (“CVD” or “metabolic diseases” or “psychotic and neurodegenerative disorders” or “cancer”), and inflammation (“Inflammatory” or “cytokines”). We make a brief summary of stress and inflammation in the field of stress-related diseases. On the basis of these reports, we further hypothesize that inflammation may be one of the common pathways of stress-related diseases. 傳統(tǒng)的觀點(diǎn)認(rèn)為壓力和疾病之間的聯(lián)系主要集中在經(jīng)典的壓力系統(tǒng)——HPA軸和SNS,。而HPA軸和SNS的改變對(duì)目標(biāo)系統(tǒng)的影響主要是間接的; 因此,，將壓力和與壓力相關(guān)的疾病聯(lián)系起來(lái)的機(jī)制仍在爭(zhēng)論之中。最近,，有人提出炎癥是一種新的、且有潛力的生物機(jī)制(Rohleder, 2014),。越來(lái)越多的文獻(xiàn)表明,，過(guò)度的炎癥直接促進(jìn)了壓力相關(guān)疾病的病理生理。在這篇綜述文章中,，檢索詞是以下組合(文獻(xiàn)選自PubMed)：壓力 (“社會(huì)壓力”或“社會(huì)心理壓力”或“心理生理壓力”或“精神壓力”)，疾病 (“CVD”或“代謝性疾病”或“精神病和神經(jīng)退行性疾病”或“癌癥”),，以及炎癥 (“炎癥”或“細(xì)胞因子”),。本文就壓力相關(guān)疾病領(lǐng)域內(nèi)的壓力和炎癥做了一個(gè)簡(jiǎn)單的總結(jié)。在這些報(bào)告的基礎(chǔ)上,，我們進(jìn)一步假設(shè)，炎癥可能是壓力相關(guān)疾病的共同途徑之一,。 大量證據(jù)表明,，壓力可以激活大腦及周邊的炎癥反應(yīng) (Rohleder, 2014; Calcia et al., 2016),。 神經(jīng)內(nèi)分泌和免疫系統(tǒng)之間存在互相聯(lián)系(Jiang et al., 1998; Quan and Banks, 2007)。壓力刺激下丘腦分泌促腎上腺皮質(zhì)激素釋放激素（CRH）激活HPA軸，CRH通常通過(guò)從腎上腺釋放糖皮質(zhì)激素（GCs）來(lái)抑制免疫反應(yīng),。GCs是應(yīng)激反應(yīng)期間釋放的主要應(yīng)激激素之一，以其免疫抑制和抗炎特性而聞名,。1970年代和1980年代的研究表明，GCs抑制淋巴細(xì)胞增殖和細(xì)胞毒性,。此外,，GC降低幾種促炎細(xì)胞因子（例如,，腫瘤壞死因子α（TNF-α）,，白細(xì)胞介素-6（IL-6））的表達(dá)，并增強(qiáng)抗炎細(xì)胞因子（例如IL-10,，TNF-β）的表達(dá) (Sorrells et al., 2009),。然而,，最近的研究人員已經(jīng)證明,，GCs對(duì)免疫系統(tǒng)也有促炎作用(Elenkov, 2008),?；A(chǔ)血漿皮質(zhì)酮水平較高的大鼠具有更多PGE2的堆積，而在急性應(yīng)激后顯示出較少的抗炎因子 (Pérez-Nievas et al., 2007),。GCs增強(qiáng)炎癥體NLRP3的表達(dá)和功能,，促進(jìn)IL-1β響應(yīng)ATP的分泌。炎癥體是細(xì)胞質(zhì)多蛋白復(fù)合物,，可感知外源性和內(nèi)源性危險(xiǎn)信號(hào),，并將促炎細(xì)胞因子裂解為成熟的細(xì)胞因子，如IL-1β和IL-18,。這項(xiàng)工作證明了GCs的促炎作用,，增強(qiáng)了先天免疫系統(tǒng)對(duì)危險(xiǎn)信號(hào)的激活(Busillo et al., 2011)。循環(huán)中的促炎因子如IL-1,，IL-6和TNFα直接刺激垂體 - 腎上腺軸,，導(dǎo)致血清中促腎上腺皮質(zhì)激素（ACTH）和GCs的水平升高，這反過(guò)來(lái)又抑制了這些促炎因子的產(chǎn)生 (Alley et al., 2006; Danese et al., 2007; Steptoe et al., 2007; Miller et al., 2008)）,。免疫系統(tǒng)和HPA軸的相互作用形成內(nèi)分泌負(fù)反饋回路,。然而，當(dāng)細(xì)胞因子在某些疾病中被過(guò)度刺激時(shí),，這些負(fù)反饋回路可能會(huì)因細(xì)胞質(zhì)GC受體（GR）水平降低和GR驅(qū)動(dòng)的抗炎基因表達(dá)減少而被削弱,，從而導(dǎo)致GCs的低反應(yīng)性 (Sterling and Eyer, 1988)。除GCs外,，SNS及其主要的神經(jīng)遞質(zhì),，去甲腎上腺素（NE）和神經(jīng)肽Y（NPY），可以調(diào)節(jié)免疫和炎癥功能,。NE通過(guò)α受體依賴的途徑增加有絲分裂原活化蛋白激酶（MAPKs）的磷酸化來(lái)促進(jìn)炎癥因子的分泌,，NPY可以通過(guò)Y1受體在巨噬細(xì)胞樣細(xì)胞系RAW264.7中引發(fā)轉(zhuǎn)化生長(zhǎng)因子β（TGF-β）和TNFα產(chǎn)生 (Alley et al., 2006; Danese et al., 2007; Steptoe et al., 2007; Miller et al., 2008)）。 促炎和抗炎機(jī)制都取決于壓力源的類型和強(qiáng)度,。急性壓力源似乎可以增強(qiáng)免疫功能,，而慢性壓力源是抑制性的。強(qiáng)烈的壓力源會(huì)過(guò)度激活免疫系統(tǒng),，導(dǎo)致炎癥和抗炎失衡,。來(lái)自不同實(shí)驗(yàn)室的報(bào)告證實(shí)了由壓力誘發(fā)的促炎癥，包括C-反應(yīng)蛋白（CRP）,，IL-6,，TNFα，IL-1β和“核因子kappa B（NF-κB）”的轉(zhuǎn)錄因子(Miller et al., 2009),。 除了外周炎癥外,，在壓力條件下也發(fā)現(xiàn)了中樞炎癥，即神經(jīng)炎癥(García-Bueno et al., 2008; Munhoz et al., 2008),。暴露在心理壓力下,，大腦中檢測(cè)到促炎細(xì)胞因子升高，小膠質(zhì)細(xì)胞活化增加,，以及外周來(lái)源的單核細(xì)胞和巨噬細(xì)胞的堆積(Johnson et al., 2005),。作為腦部駐留的巨噬細(xì)胞,，小膠質(zhì)細(xì)胞被認(rèn)為是主要的促炎細(xì)胞因子來(lái)源。壓力誘發(fā)的小膠質(zhì)細(xì)胞是通過(guò)直接和間接機(jī)制進(jìn)行激活的,。小膠質(zhì)細(xì)胞同時(shí)表達(dá)GC和鹽皮質(zhì)激素受體,，因此小膠質(zhì)細(xì)胞可能對(duì)皮質(zhì)酮峰值有直接反應(yīng) (Calcia et al., 2016)。此外,，GC受體也高度存在于海馬體和前額葉皮層中,，因此壓力誘導(dǎo)的皮質(zhì)酮可能對(duì)小膠質(zhì)細(xì)胞產(chǎn)生間接影響。除此之外,，最近的一項(xiàng)研究表明,，中樞神經(jīng)系統(tǒng)的先天免疫系統(tǒng)可以對(duì)急性應(yīng)激源做出反應(yīng)，從而在大腦中釋放危險(xiǎn)信號(hào)高遷移性組box-1（HMGB-1）,，通過(guò)作用于NLRP3炎癥體來(lái)刺激小膠質(zhì)細(xì)胞,，為IL-1β分泌做準(zhǔn)備 (Weber et al., 2015)。 被激活的小膠質(zhì)細(xì)胞顯示出肥厚的分支形態(tài),，伴有增大的體細(xì)胞,，并產(chǎn)生夸張的細(xì)胞因子以募集外周單核細(xì)胞。大腦巨噬細(xì)胞和循環(huán)單核細(xì)胞的增加有助于大腦中促炎細(xì)胞因子產(chǎn)生（即IL-1β,，TNFα，IL-6）水平升高(Wohleb and Delpech, 2016),。 In common, over-activated immune system, increased activity through SNS pathways, and reduced GCs responsiveness may work tandemly in the activation of inflammatory responses during stress. GCs, catecholamines, cytokines and other mediators released by stress are thought to be the main mediators in stress-induced pro-inflammatory effect. 通常,，過(guò)度激活的免疫系統(tǒng)，通過(guò)SNS途徑增加的活動(dòng)以及GCs反應(yīng)性降低可能在壓力期間協(xié)同激活炎癥反應(yīng),。GCs,，兒茶酚胺，細(xì)胞因子和應(yīng)激釋放的其他介質(zhì)被認(rèn)為是壓力誘導(dǎo)的促炎效應(yīng)的主要介質(zhì),。 Classically, inflammation is classically known as the crucial response to microbe invasion or tissue injury to keep maintenance of tissue homeostasis. In recent years, our knowledge of the inflammation role is greatly enlarged. Inflammatory pathway has been recognized as a pivotal molecular basis in the pathogenesis of many chronic diseases. By far, increasing literatures have shown that excessive inflammation play critical roles in the progression, and/or onset of stress-related diseases. There has been a growing number of evidence supporting that inflammatory response constitutes the “common soil” of the multifactorial diseases, including cardiovascular and metabolic diseases, psychotic neurodegenerative disorders and cancer (Scrivo et al., 2011). 傳統(tǒng)認(rèn)知中，炎癥通常被認(rèn)為是應(yīng)對(duì)微生物侵襲或組織損傷的關(guān)鍵反應(yīng),，以維持組織的平衡狀態(tài)。近年來(lái),，我們對(duì)炎癥作用的認(rèn)識(shí)有了很大的提高,。炎癥通路已被公認(rèn)為許多慢性疾病發(fā)病機(jī)制中一個(gè)關(guān)鍵的分子基礎(chǔ),。到目前為止,，越來(lái)越多的文獻(xiàn)表明,，過(guò)度的炎癥在壓力相關(guān)疾病的進(jìn)展和/或發(fā)病中起著關(guān)鍵作用,。越來(lái)越多的證據(jù)支持炎癥反應(yīng)構(gòu)成了多因素疾病的“共同土壤”,，包括心血管和代謝疾病，精神病性神經(jīng)退行性疾病和癌癥(Scrivo et al., 2011),。 越來(lái)越多的研究表明,，過(guò)度炎癥在壓力和與壓力相關(guān)疾病之間起著關(guān)鍵作用,。雖然壓力和炎癥，或炎癥和疾病已經(jīng)得到了廣泛而很好的討論,，但很少有文獻(xiàn)在同時(shí)關(guān)注這三個(gè)因素（壓力,，炎癥和疾病）,。在這一部分,，我們將討論不同壓力相關(guān)疾病中的炎癥，并探索其內(nèi)部機(jī)制（表1）,。 TABLE 1
Table 1. Stress substance that link stress and various diseases. 表1
表1：將壓力和各種疾病聯(lián)系起來(lái)的壓力性物質(zhì) CVD was considered to be a leading cause of death worldwide. Large bodies of clinical trial pointed out that chronic stress, whether early life stress (Su et al., 2015) or adult stress has long been linked to increased coronary heart disease (CHD) risk. Childhood adversity especially severe physical and sexual abuse in childhood was found to strongly relate to higher morbidity of cardiovascular events in women (Rich-Edwards et al., 2012; Thurston et al., 2014). Children who are less expressive and cohesive in their original family exhibited more problematic cardiovascular risk factor profiles (Bleil et al., 2013). Those who experienced more family disruption events or early life family conflict had greater mean intima-media thickness (IMT), a subclinical marker of CVD risk (Bleil et al., 2013). In adulthood, work-related stressors such as low-income, high job demands combined with low control, shift work and workplace conflicts were mostly reported to be correlated to higher CVD risk (Bleil et al., 2013). Besides that, poor sleep quality under stress, discrimination emotion stress, such as anger, hostility and aggressiveness were also involved in coronary artery disease (Kop, 2003). On the contrast, effective stress management including positive emotions, optimism and life satisfaction were proved to have protective roles for CVD (Bleil et al., 2013). 心血管疾病被認(rèn)為是在全世界范圍內(nèi)造成死亡的主要原因。大量的臨床試驗(yàn)指出,，慢性壓力,，無(wú)論是早期生活壓力(Su et al., 2015)還是成年壓力，長(zhǎng)期以來(lái)都與冠心?。–HD）風(fēng)險(xiǎn)增加有關(guān),。 童年逆境特別是兒童時(shí)期嚴(yán)重的身體和性虐待與女性心血管事件的發(fā)病率較高密切相關(guān)(Rich-Edwards et al., 2012; Thurston et al., 2014)。在原有家庭中表達(dá)力和凝聚力較差的兒童表現(xiàn)出更多的心血管危險(xiǎn)因素特征(Bleil et al., 2013),。那些經(jīng)歷過(guò)更多家庭破裂事件或早期生活家庭沖突的人具有更大的平均內(nèi)膜-中層厚度（IMT）,，這是CVD風(fēng)險(xiǎn)的亞臨床標(biāo)志物(Bleil et al., 2013)。 在成年后,，與工作相關(guān)的壓力因素,，如低收入，高工作需求,，加上低控制度,，輪班工作和工作場(chǎng)所沖突，大多與較高的CVD風(fēng)險(xiǎn)相關(guān) (Bleil et al., 2013),。除此之外,，在壓力下睡眠質(zhì)量差，歧視性情緒壓力,，如憤怒,，敵意和攻擊性也與冠狀動(dòng)脈疾病有關(guān)(Kop, 2003),。相比之下，有效的壓力管理,，包括積極的情緒,，樂(lè)觀和生活滿意度被證實(shí)對(duì)CVD具有保護(hù)作用 (Bleil et al., 2013)。 While the biological mechanisms of stress increasing CVD risk are not well-known, chronic low-grade inflammatory load may emerge as a possible link as it is both elevated by chronic stress and contributed to early process, progression and thrombotic complications of atherosclerosis. IL-6 and CRP, the two important biomarkers of systematic inflammation, are considered indicative and potentially predictive for atherosclerosis (Tsirpanlis, 2005;Nadrowski et al., 2016). Coincidently, these two inflammatory indicators were elevated in different types of life stress. For instance, severe levels of childhood abuse were associated with a more elevated acute stress-induced IL-6 response, possibly due to reduced methylation of the IL-6 promoter (Janusek et al., 2017). Adults who had greater childhood adversity was reported to have more depressive symptoms and elevated concentrations of CRP (Janusek et al., 2017). Recent studies have suggested that CRP and IL-6 are mechanisms by which early adversity may contribute to CVD (Ridker et al., 2002; Albert et al., 2006; Graham et al., 2006). Work-related stressors have also been mentioned to correlate with elevated CRP and IL-6 (von K?nel et al., 2008). In a recent study applied in black and white men, greater stressor-evoked reduction in high-frequency heart rate variability (HF-HRV) and were correlated with higher CRP and IL-6. In animal stress models (social isolation, social disruption, cold stress, severe chronic unpredictable stress), increased plaque size, elevated serum IL-6, NPY levels were observed. However, when single supplied with GC after Adrenalectomy, plaque size and serum inflammatory factors were decreased or did not change. This suggested that the possible mechanisms of stress-related inflammation in CVD may include SNS-mediated increases in NE and NPY. Noisy communities as life stressor induces significant increase in urine epinephrine and NE leading to hypertension (Seidman and Standring, 2010). NE promoted the production of inflammatory factors by facilitating the phosphorylation of MAPKs through activation of NE α receptor (Huang et al., 2012). NPY could elicit TGF-β1 and TNFα production in macrophage-like cell line RAW264.7 via Y1 receptor (von K?nel et al., 2008). NPY could also directly activate the HMGB1 release and cytoplasmic translocation from the macrophage (Zhou et al., 2013). Inflammation has also been shown to correlate with endothelial dysfunction and relate to the renin-angiotensin system (Li et al., 2012). 雖然壓力增加心血管疾病風(fēng)險(xiǎn)的生物學(xué)機(jī)制尚不清楚,，但慢性低度炎癥性負(fù)荷可能成為一種潛在關(guān)聯(lián),，因?yàn)樗纫蚵詨毫Χ撸执俪闪藙?dòng)脈粥樣硬化的早期過(guò)程,，進(jìn)展和血栓并發(fā)癥,。IL-6和CRP是系統(tǒng)性炎癥的兩個(gè)重要生物標(biāo)志物，被認(rèn)為對(duì)動(dòng)脈粥樣硬化具有指示性和潛在預(yù)測(cè)性(Tsirpanlis, 2005; Nadrowski et al., 2016),。巧合的是,，這兩種炎癥指標(biāo)在不同類型的生活壓力下會(huì)隨之升高。例如,，嚴(yán)重的童年虐待與急性應(yīng)激誘導(dǎo)的IL-6反應(yīng)的升高有關(guān),，可能是由于IL-6啟動(dòng)子的甲基化程度降低了 (Janusek et al., 2017)。據(jù)報(bào)道,，具有更大童年逆境的成年人具有更多的抑郁癥狀和更高的CRP濃度 (Janusek et al., 2017),。最近的研究表明，CRP和IL-6是早期逆境可能導(dǎo)致CVD的機(jī)制(Ridker et al., 2002; Albert et al., 2006; Graham et al., 2006),。工作相關(guān)的壓力因素也被提到與CRP和IL-6的升高相關(guān) (von K?nel et al., 2008),。 在最近應(yīng)用于黑人和白人男性的研究中，更大的壓力源誘發(fā)的高頻心率變異性（HF-HRV）的減少與較高的CRP和IL-6相關(guān)聯(lián),。在動(dòng)物壓力模型（社會(huì)孤立,，社會(huì)混亂，寒冷壓力,，嚴(yán)重的慢性不可預(yù)測(cè)的壓力）中,，觀察到斑塊大小增加，血清IL-6升高,，NPY水平升高,。然而，當(dāng)腎上腺切除術(shù)后單一供應(yīng)GC時(shí),，斑塊大小和血清炎癥因子減少或沒(méi)有改變,。這表明心血管疾病中與壓力相關(guān)的炎癥的機(jī)制，可能包括SNS介導(dǎo)的NE和NPY的增加,。嘈雜的社區(qū)作為生活壓力源會(huì)誘發(fā)尿液中腎上腺素和NE顯著增加,，導(dǎo)致高血壓 (Seidman and Standring, 2010)。NE通過(guò)激活NE α受體促進(jìn)MAPKs的磷酸化來(lái)促進(jìn)炎癥因子的產(chǎn)生(Huang et al., 2012)。NPY可以通過(guò)Y1受體在巨噬細(xì)胞樣細(xì)胞系RAW264.7中激發(fā)TGF-β1和TNFα的產(chǎn)生(von K?nel et al., 2008),。NPY還可以直接激活巨噬細(xì)胞的HMGB1釋放和細(xì)胞質(zhì)轉(zhuǎn)移 (Zhou et al., 2013),。炎癥也被證實(shí)與內(nèi)皮功能障礙相關(guān)，并與腎素 - 血管緊張素系統(tǒng)有關(guān) (Li et al., 2013),。 總體而言,，可能的機(jī)制可歸納如下。壓力可以通過(guò)SNS系統(tǒng)激活,，釋放NE和NPY,，這兩種壓力激素進(jìn)一步促進(jìn)MAPKs的磷酸化或HMGB1的釋放，因此誘發(fā)系統(tǒng)性炎癥（IL-6,，CRP）,，促進(jìn)或加速心血管疾病的發(fā)展?？寡姿幙赡芘c常規(guī)抗高血壓藥在預(yù)防和治療壓力相關(guān)的心血管疾病方面具有協(xié)同作用。 壓力事件可能會(huì)促使人們選擇不健康的食物(Kuo et al., 2008),。通常病態(tài)肥胖、2型糖尿病,、代謝綜合征及非酒精性脂肪肝都與這些不健康的食物相關(guān)(Mikolajczyk et al., 2009),。壓力會(huì)增強(qiáng)餐后甘油三酯的峰值并延緩脂質(zhì)清除 (Kiecolt-Glaser, 2010)。正如Hoorn的研究所示,，未被發(fā)現(xiàn)的2型糖尿病的較高患病率與生活中的壓力事件造成的長(zhǎng)期心理壓力有關(guān)(Mooy et al., 2000),。最近的一項(xiàng)前瞻性研究支持了這一觀點(diǎn)，并提供了進(jìn)一步的證據(jù)(Cosgrove et al., 2012),。此外,，在臨床上，有效的壓力管理訓(xùn)練或基于正念的減壓訓(xùn)練已被證實(shí)對(duì)2型糖尿病患者具有顯著益處,。相反,，高度焦慮的患者沒(méi)有從訓(xùn)練中獲得更多的改善 (Rosenzweig et al., 2007)。 Insulin resistance frequently develops during acute or chronic stress (Tsuneki et al., 2013). Insufficient insulin secretion to compensate for insulin resistance is also the characteristic of Type 2 diabetes. Insulin resistance, visceral obesity, dyslipidemia, type 2 diabetes mellitus and metabolic syndrome are key risk factors in the development and progression of NAFLD. At the intersection of metabolism and immunity, inflammation may be an important link between stress and metabolic disease. Intense stress over-activates the immune system, leading to the imbalance between inflammation and anti-inflammation. The activated stress pathways can initiate or exacerbate inflammation and culminate in hepatocyte cell death and liver damage by apoptosis (Gentile et al., 2011). IL-1 family members might be involved in controlling insulin resistance and metabolic inflammation in various obesity-associated disorders (Kamari et al., 2011; Tilg and Moschen, 2011; Tack et al., 2012). It is reported that the modulator of IL-1, NLRP6 and NLRP3 inflammasomes negatively regulate NAFLD/NASH progression, as well as multiple aspects of metabolic syndrome (Zhu et al., 2006). Inflammatory transcriptor NF-κB and JNK activator protein-1 (AP-1) emerged as a central metabolic regulator (Wellen and Hotamisligil, 2005). Enhanced hepatic NF-κB activity was observed in high fat fed-mice (Day, 2006). NAFLD is regularly associated with lipometabolic disorders and inflammatory reactions, especially in the nonalcoholic steatohepatitis (NASH) stage (Liu et al., 2012). Chronic, low-grade inflammatory process is also the characteristic of diabetes. The “two-hit” hypothesis for the pathogenesis of NAFLD implicates inflammation as the link between steatosis and steatohepatitis. Inflammatory stress may aggravate the progression of NAFLD by increasing cholesterol influx and reducing cholesterol efflux especially during the second-hit stage of NAFLD (Ma et al., 2008). 胰島素抵抗經(jīng)常在急性或慢性壓力下發(fā)展 (Tsuneki et al., 2013),。補(bǔ)償胰島素抵抗的胰島素分泌不足也是2型糖尿病的特征,。胰島素抵抗、內(nèi)臟肥胖,、血脂異常,、2型糖尿病和代謝綜合征是非酒精性脂肪肝發(fā)生和進(jìn)展的關(guān)鍵風(fēng)險(xiǎn)因素。在代謝和免疫的交叉點(diǎn)上,，炎癥可能是壓力和代謝疾病之間的一個(gè)重要環(huán)節(jié),。 強(qiáng)烈的壓力會(huì)過(guò)度激活免疫系統(tǒng)，導(dǎo)致炎癥和抗炎之間的不平衡。 被激活的應(yīng)激通路可以引發(fā)或加劇炎癥,，并最終導(dǎo)致肝細(xì)胞死亡和細(xì)胞凋亡引起的肝損傷 (Gentile et al., 2011),。IL-1家族成員可能參與控制各種肥胖相關(guān)疾病中的胰島素抵抗和代謝性炎癥 (Kamari et al., 2011; Tilg and Moschen, 2011; Tack et al., 2012)）。據(jù)報(bào)道,，IL-1,，NLRP6和NLRP3炎癥體的調(diào)節(jié)劑對(duì)非酒精性脂肪肝/非酒精性脂肪性肝炎的進(jìn)展以及代謝綜合征的多個(gè)方面進(jìn)行了負(fù)向調(diào)節(jié) (Zhu et al., 2006)。 炎癥轉(zhuǎn)錄因子NF-κB和JNK激活蛋白-1（AP-1）成為了中樞代謝的調(diào)節(jié)劑 (Wellen and Hotamisligil, 2005),。在高脂肪喂養(yǎng)小鼠中觀察到肝臟NF-κB活性增強(qiáng) (Day, 2006),。非酒精性脂肪肝通常與脂質(zhì)代謝性疾病和炎癥反應(yīng)有關(guān)，特別是在非酒精性脂肪性肝炎（NASH）階段 (Liu et al., 2012),。 慢性,、低級(jí)別的炎癥過(guò)程也是糖尿病的特征。非酒精性脂肪肝發(fā)病機(jī)制的“雙擊”假說(shuō)將炎癥作為脂肪變性和脂肪性肝炎之間的聯(lián)系,。炎癥壓力可能通過(guò)增加膽固醇的流入和減少膽固醇的流出來(lái)加劇非酒精性脂肪肝的進(jìn)展,，特別是在非酒精性脂肪肝的第二重打擊階段(Ma et al., 2008)。 Metabolism-controlling stress hormones, especially GCs and NE could exert anti-insulin effects, and in the long run induce insulin resistance. GC receptor antagonist RU486 and adrenalectomy reduce the occurrence of insulin resistance. High concentration of NE in plasma could raise fasting glucose and reduce glucose tolerance, possibly mediated by lipolysis and increased fatty acid concentrations (Marangou et al., 1988). Adrenergic receptor activation may directly affect the insulin signaling pathway or cellular glucose transport (Mulder et al., 2005). Additionally, GCs and NE could also regulate inflammation. In diabetes, elevated circulating levels of proinflammatory cytokines are originally thought to be the adipocytes themselves in response to obesity. However, an increasing number of evidence suggests that obesity results in increased number of macrophages and changes in the activation status of these cells. Therefore, adipose tissue macrophages produce a significant proportion of the inflammatory factors that are upregulated by obesity (Donath and Shoelson, 2011). Inflammatory cytokines produced by various cells such as Kupffer cells, macrophages, neutrophils, monocytes, adipocytes and hepatocytes, have critical roles in lipid metabolism and hepatic inflammation that promote liver damage. Antagonizing or inhibiting TNFα, significantly improved NAFLD and is currently tested in human NASH (chronic hepatic inflammation; Gastaldelli et al., 2009; Musso et al., 2009). Furthermore, TNFR1 ectodomain shedding could attenuate the progression from “simple steatosis” towards NASH (Aparicio-Vergara et al., 2013). 控制代謝的應(yīng)激激素,，特別是GCs和NE可以發(fā)揮抗胰島素的作用,，從長(zhǎng)遠(yuǎn)來(lái)看會(huì)誘發(fā)胰島素抵抗。GC受體拮抗劑RU486和腎上腺切除術(shù)可減少胰島素抵抗的發(fā)生,。血漿中高濃度的NE可以提高空腹血糖并降低葡萄糖耐量,，可能是由脂肪分解和脂肪酸濃度的增加所介導(dǎo)的 (Marangou et al., 1988)。腎上腺素受體的激活可能直接影響胰島素信號(hào)通路或細(xì)胞葡萄糖轉(zhuǎn)運(yùn)(Mulder et al., 2005),。此外,，GCs和NE也可以調(diào)節(jié)炎癥。在糖尿病中,，促炎癥細(xì)胞因子的循環(huán)水平升高最初被認(rèn)為是脂肪細(xì)胞本身對(duì)肥胖的反應(yīng),。然而，越來(lái)越多的證據(jù)表明,，肥胖會(huì)導(dǎo)致巨噬細(xì)胞數(shù)量的增加及其活化狀態(tài)的變化,。因此，脂肪組織巨噬細(xì)胞產(chǎn)生了相當(dāng)一部分因肥胖而上調(diào)的炎癥因子(Donath and Shoelson, 2011),。由各種細(xì)胞產(chǎn)生的炎癥細(xì)胞因子,，如Kupffer細(xì)胞，巨噬細(xì)胞,，中性粒細(xì)胞,，單核細(xì)胞，脂肪細(xì)胞和肝臟細(xì)胞,，在促進(jìn)肝損傷的脂質(zhì)代謝和肝臟炎癥中起著關(guān)鍵作用,。拮抗或抑制TNFα,，顯著改善非酒精性脂肪肝，目前正在慢性肝炎人群中進(jìn)行人體測(cè)試 (Gastaldelli et al., 2009; Musso et al., 2009),。此外,，TNFR1外域脫落可以減弱從“單純脂肪變性”向慢性肝炎的進(jìn)展 (Aparicio-Vergara et al., 2013)。 Albert M. A., Glynn R. J., Buring J., Ridker P. M. (2006). Impact of traditional and novel risk factors on the relationship between socioeconomic status and incident cardiovascular events. Circulation 114, 2619–2626. 10.1161/circulationaha.106.660043 Alley D. E., Seeman T. E., Ki Kim J., Karlamangla A., Hu P., Crimmins E. M. (2006). Socioeconomic status and C-reactive protein levels in the US population: NHANES IV. Brain Behav. Immun. 20, 498–504. 10.1016/j.bbi.2005.10.003 Angelo L. S., Talpaz M., Kurzrock R. (2002). Autocrine interleukin-6 production in renal cell carcinoma: evidence for the involvement of p53. Cancer Res. 62, 932–940. Aparicio-Vergara M., Hommelberg P. P. H., Schreurs M., Gruben N., Stienstra R., Shiri-Sverdlov R., et al.. (2013). Tumor necrosis factor receptor 1 gain-of-function mutation aggravates nonalcoholic fatty liver disease but does not cause insulin resistance in a murine model. Hepatology 57, 566–576. 10.1002/hep.26046 Barbieri A., Bimonte S., Palma G., Luciano A., Rea D., Giudice A., et al.. (2015). The stress hormone norepinephrine increases migration of prostate cancer cells in vitro and in vivo. Int. J. Oncol. 47, 527–534. 10.3892/ijo.2015.3038 Bellinger D. L., Millar B. A., Perez S., Carter J., Wood C., ThyagaRajan S., et al.. (2008). Sympathetic modulation of immunity: relevance to disease. Cell. Immunol. 252, 27–56. 10.1016/j.cellimm.2007.09.005 Bencherif M., Lippiello P. M., Lucas R., Marrero M. B. (2011). α7 nicotinic receptors as novel therapeutic targets for inflammation-based diseases. Cell. Mol. Life Sci. 68, 931–949. 10.1007/s00018-010-0525-1 Bleil M. E., Adler N. E., Appelhans B. M., Gregorich S. E., Sternfeld B., Cedars M. I. (2013). Childhood adversity and pubertal timing: understanding the origins of adulthood cardiovascular risk. Biol. Psychol. 93, 213–219. 10.1016/j.biopsycho.2013.02.005 Brenner D. R., Fanidi A., Grankvist K., Muller D. C., Brennan P., Manjer J., et al.. (2017). Inflammatory cytokines and lung cancer risk in 3 prospective studies. Am. J. Epidemiol. 185, 86–95. 10.1093/aje/kww159 Busillo J. M., Azzam K. M., Cidlowski J. A. (2011). Glucocorticoids sensitize the innate immune system through regulation of the NLRP3 inflammasome. J. Biol. Chem. 286, 38703–38713. 10.1074/jbc.M111.275370 Calcia M. A., Bonsall D. R., Bloomfield P. S., Selvaraj S., Barichello T., Howes O. D. (2016). Stress and neuroinflammation: a systematic review of the effects of stress on microglia and the implications for mental illness. Psychopharmacology (Berl) 233, 1637–1650. 10.1007/s00213-016-4218-9 Capuron L., Raison C. L., Musselman D. L., Lawson D. H., Nemeroff C. B., Miller A. H. (2003). Association of exaggerated HPA axis response to the initial injection of interferon-α with development of depression during interferon-α therapy. Am. J. Psychiatry 160, 1342–1345. 10.1176/appi.ajp.160.7.1342 Chen C.-H., Zhou W., Liu S., Deng Y., Cai F., Tone M., et al.. (2012). Increased NF-κB signalling up-regulates BACE1 expression and its therapeutic potential in Alzheimer’s disease. Int. J. Neuropsychopharmacol. 15, 77–90. 10.1017/S1461145711000149 Chung Y.-C., Chang Y.-F. (2003). Serum interleukin-6 levels reflect the disease status of colorectal cancer. J. Surg. Oncol. 83, 222–226. 10.1002/jso.10269 Cohen S., Janicki-Deverts D., Miller G. E. (2007). Psychological stress and disease. JAMA 298, 1685–1687. 10.1001/jama.298.14.1685 Comi C., Carecchio M., Chiocchetti A., Nicola S., Galimberti D., Fenoglio C., et al.. (2010). Osteopontin is increased in the cerebrospinal fluid of patients with Alzheimer’s disease and its levels correlate with cognitive decline. J. Alzheimers Dis. 19, 1143–1148. 10.3233/JAD-2010-1309 Cosgrove M. P., Sargeant L. A., Caleyachetty R., Griffin S. J. (2012). Work-related stress and Type 2 diabetes: systematic review and meta-analysis. Occup. Med. (Lond) 62, 167–173. 10.1093/occmed/kqs002 Danese A., Pariante C. M., Caspi A., Taylor A., Poulton R. (2007). Childhood maltreatment predicts adult inflammation in a life-course study. Proc. Natl. Acad. Sci. U S A 104, 1319–1324. 10.1073/pnas.0610362104 Day C. P. (2006). Non-alcoholic fatty liver disease: current concepts and management strategies. Clin. Med. 6, 19–25. 10.7861/clinmedicine.6-1-19 Donath M. Y., Shoelson S. E. (2011). Type 2 diabetes as an inflammatory disease. Nat. Rev. Immunol. 11, 98–107. 10.1038/nri2925 Dowlati Y., Herrmann N., Swardfager W., Liu H., Sham L., Reim E. K., et al.. (2010). A meta-analysis of cytokines in major depression. Biol. Psychiatry 67, 446–457. 10.1016/j.biopsych.2009.09.033 Elenkov I. J. (2008). Neurohormonal-cytokine interactions: implications for inflammation, common human diseases and well-being. Neurochem. Int. 52, 40–51. 10.1016/j.neuint.2007.06.037 Gao S. P., Mark K. G., Leslie K., Pao W., Motoi N., Gerald W. L., et al.. (2007). Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas. J. Clin. Invest. 117, 3846–3856. 10.1172/jci31871 García-Bueno B., Caso J. R., Leza J. C. (2008). Stress as a neuroinflammatory condition in brain: damaging and protective mechanisms. Neurosci. Biobehav. Rev. 32, 1136–1151. 10.1016/j.neubiorev.2008.04.001 Gastaldelli A., Harrison S. A., Belfort-Aguilar R., Hardies L. J., Balas B., Schenker S., et al.. (2009). Importance of changes in adipose tissue insulin resistance to histological response during thiazolidinedione treatment of patients with nonalcoholic steatohepatitis. Hepatology 50, 1087–1093. 10.1002/hep.23116 Gentile C. L., Nivala A. M., Gonzales J. C., Pfaffenbach K. T., Wang D., Wei Y., et al.. (2011). Experimental evidence for therapeutic potential of taurine in the treatment of nonalcoholic fatty liver disease. Am. J. Physiol. Regul. Integr. Comp. Physiol. 301, R1710–R1722. 10.1152/ajpregu.00677.2010 Graham J. E., Christian L. M., Kiecolt-Glaser J. K. (2006). Stress, age, and immune function: toward a lifespan approach. J. Behav. Med. 29, 389–400. 10.1007/s10865-006-9057-4 Grimaldi L. M., Casadei V. M., Ferri C., Veglia F., Licastro F., Annoni G., et al.. (2000). Association of early-onset Alzheimer’s disease with an interleukin-1α gene polymorphism. Ann. Neurol. 47, 361–365. 10.1002/1531-8249(200003)47:3<361::AID-ANA12>3.0.CO;2-N Grivennikov S., Karin E., Terzic J., Mucida D., Yu G.-Y., Vallabhapurapu S., et al.. (2009). IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell 15, 103–113. 10.1016/j.ccr.2009.01.001 Heikkil? K., Ebrahim S., Lawlor D. A. (2008). Systematic review of the association between circulating interleukin-6 (IL-6) and cancer. Eur. J. Cancer 44, 937–945. 10.1016/j.ejca.2008.02.047 Henry C. J., Huang Y., Wynne A., Hanke M., Himler J., Bailey M. T., et al.. (2008). Minocycline attenuates lipopolysaccharide (LPS)-induced neuroinflammation, sickness behavior, and anhedonia. J. Neuroinflammation 5:15. 10.1186/1742-2094-5-15 Hirano T., Ishihara K., Hibi M. (2000). Roles of STAT3 in mediating the cell growth, differentiation and survival signals relayed through the IL-6 family of cytokine receptors. Oncogene 19, 2548–2556. 10.1038/sj.onc.1203551 Hoshino T., Namba T., Takehara M., Nakaya T., Sugimoto Y., Araki W., et al.. (2009). Prostaglandin E2 stimulates the production of amyloid-β peptides through internalization of the EP4 receptor. J. Biol. Chem. 284, 18493–18502. 10.1074/jbc.M109.003269 Huang J.-L., Zhang Y.-L., Wang C.-C., Zhou J.-R., Ma Q., Wang X., et al.. (2012). Enhanced phosphorylation of MAPKs by NE promotes TNF-α production by macrophage through α adrenergic receptor. Inflammation 35, 527–534. 10.1007/s10753-011-9342-4 Janusek L. W., Tell D., Gaylord-Harden N., Mathews H. L. (2017). Relationship of childhood adversity and neighborhood violence to a proinflammatory phenotype in emerging adult African American men: an epigenetic link. Brain Behav. Immun. 60, 126–135. 10.1016/j.bbi.2016.10.006 Jiang C. L., Lu C. L., Liu X. Y. (1998). The molecular basis for bidirectional communication between the immune and neuroendocrine systems. Domest. Anim. Endocrinol. 15, 363–369. 10.1016/s0739-7240(98)00026-5 Johnson M. (2006). Molecular mechanisms of β2-adrenergic receptor function, response, and regulation. J. Allergy Clin. Immunol. 117, 18–24; quiz 25. 10.1016/j.jaci.2005.11.012 Johnson J. D., Campisi J., Sharkey C. M., Kennedy S. L., Nickerson M., Greenwood B. N., et al.. (2005). Catecholamines mediate stress-induced increases in peripheral and central inflammatory cytokines. Neuroscience 135, 1295–1307. 10.1016/j.neuroscience.2005.06.090 Kamari Y., Shaish A., Vax E., Shemesh S., Kandel-Kfir M., Arbel Y., et al.. (2011). Lack of interleukin-1α or interleukin-1β inhibits transformation of steatosis to steatohepatitis and liver fibrosis in hypercholesterolemic mice. J. Hepatol. 55, 1086–1094. 10.1016/j.jhep.2011.01.048 Kerr L. R., Wilkinson D. A., Emerman J. T., Weinberg J. (1999). Interactive effects of psychosocial stressors and gender on mouse mammary tumor growth. Physiol. Behav. 66, 277–284. 10.1016/s0031-9384(98)00296-0 Kiecolt-Glaser J. K. (2010). Stress, food, and inflammation: psychoneuroimmunology and nutrition at the cutting edge. Psychosom. Med. 72, 365–369. 10.1097/PSY.0b013e3181dbf489 Kim-Fuchs C., Le C. P., Pimentel M. A., Shackleford D., Ferrari D., Angst E., et al.. (2014). Chronic stress accelerates pancreatic cancer growth and invasion: a critical role for β-adrenergic signaling in the pancreatic microenvironment. Brain Behav. Immun. 40, 40–47. 10.1016/j.bbi.2014.02.019 Kim T.-H., Gill N. K., Nyberg K. D., Nguyen A. V., Hohlbauch S. V., Geisse N. A., et al.. (2016). Cancer cells become less deformable and more invasive with activation of β-adrenergic signaling. J. Cell Sci. 129, 4563–4575. 10.1242/jcs.194803 Kolmus K., Tavernier J., Gerlo S. (2015). β2-Adrenergic receptors in immunity and inflammation: stressing NF-κB. Brain Behav. Immun. 45, 297–310. 10.1016/j.bbi.2014.10.007 Kop W. J. (2003). The integration of cardiovascular behavioral medicine and psychoneuroimmunology: new developments based on converging research fields. Brain Behav. Immun. 17, 233–237. 10.1016/s0889-1591(03)00051-5 Krizanova O., Babula P., Pacak K. (2016). Stress, catecholaminergic system and cancer. Stress 19, 419–428. 10.1080/10253890.2016.1203415 Kunjathoor V. V., Tseng A. A., Medeiros L. A., Khan T., Moore K. J. (2004). β-Amyloid promotes accumulation of lipid peroxides by inhibiting CD36-mediated clearance of oxidized lipoproteins. J. Neuroinflammation 1:23. 10.1186/1742-2094-1-23 Kuo L. E., Czarnecka M., Kitlinska J. B., Tilan J. U., Kvetnansky R., Zukowska Z. (2008). Chronic stress, combined with a high-fat/high-sugar diet, shifts sympathetic signaling toward neuropeptide Y and leads to obesity and the metabolic syndrome. Ann. N Y Acad. Sci. 1148, 232–237. 10.1196/annals.1410.035 Lamkin D. M., Sloan E. K., Patel A. J., Chiang B. S., Pimentel M. A., Ma J. C. Y., et al.. (2012). Chronic stress enhances progression of acute lymphoblastic leukemia via β-adrenergic signaling. Brain Behav. Immun. 26, 635–641. 10.1016/j.bbi.2012.01.013 Lamkin D. M., Sung H. Y., Yang G. S., David J. M., Ma J. C. Y., Cole S. W., et al.. (2015). α2-Adrenergic blockade mimics the enhancing effect of chronic stress on breast cancer progression. Psychoneuroendocrinology 51, 262–270. 10.1016/j.psyneuen.2014.10.004 Landsbergis P. A. (2003). The changing organization of work and the safety and health of working people: a commentary. J. Occup. Environ. Med. 45, 61–72. 10.1097/00043764-200301000-00014 Li G., Xu Y., Ling F., Liu A., Wang D., Wang Q., et al.. (2012). Angiotensin-converting enzyme 2 activation protects against pulmonary arterial hypertension through improving early endothelial function and mediating cytokines levels. Chin. Med. J. 125, 1381–1388. Lin Y., Yang X., Liu W., Li B., Yin W., Shi Y., et al.. (2017). Chemerin has a protective role in hepatocellular carcinoma by inhibiting the expression of IL-6 and GM-CSF and MDSC accumulation. Oncogene [Epub ahead of print]. 10.1038/onc.2016.516 Lippitz B. E. (2013). Cytokine patterns in patients with cancer: a systematic review. Lancet. Oncol. 14, e218–e228. 10.1016/S1470-2045(12)70582-X Liu Y., Qiu D. K., Ma X. (2012). Liver X receptors bridge hepatic lipid metabolism and inflammation. J. Dig. Dis. 13, 69–74. 10.1111/j.1751-2980.2011.00554.x Ma K. L., Ruan X. Z., Powis S. H., Chen Y., Moorhead J. F., Varghese Z. (2008). Inflammatory stress exacerbates lipid accumulation in hepatic cells and fatty livers of apolipoprotein E knockout mice. Hepatology 48, 770–781. 10.1002/hep.22423 Mace T. A., Shakya R., Pitarresi J. R., Swanson B., McQuinn C. W., Loftus S., et al.. (2016). IL-6 and PD-L1 antibody blockade combination therapy reduces tumour progression in murine models of pancreatic cancer. Gut [Epub ahead of print]. 10.1136/gutjnl-2016-311585 Mantyh P. W., Rogers S. D., Allen C. J., Catton M. D., Ghilardi J. R., Levin L. A., et al.. (1995). β 2-adrenergic receptors are expressed by glia in vivo in the normal and injured central nervous system in the rat, rabbit and human. J. Neurosci. 15, 152–164. Marangou A. G., Alford F. P., Ward G., Liskaser F., Aitken P. M., Weber K. M., et al.. (1988). Hormonal effects of norepinephrine on acute glucose disposal in humans: a minimal model analysis. Metab. Clin. Exp. 37, 885–891. 10.1016/0026-0495(88)90124-2 Mikolajczyk R. T., El Ansari W., Maxwell A. E. (2009). Food consumption frequency and perceived stress and depressive symptoms among students in three European countries. Nutr. J. 8:31. 10.1186/1475-2891-8-31 Miller G. E., Chen E., Sze J., Marin T., Arevalo J. M. G., Doll R., et al.. (2008). A functional genomic fingerprint of chronic stress in humans: blunted glucocorticoid and increased NF-κB signaling. Biol. Psychiatry 64, 266–272. 10.1016/j.biopsych.2008.03.017 Miller A. H., Maletic V., Raison C. L. (2009). Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol. Psychiatry 65, 732–741. 10.1016/j.biopsych.2008.11.029 Miura H., Ozaki N., Sawada M., Isobe K., Ohta T., Nagatsu T. (2008). A link between stress and depression: shifts in the balance between the kynurenine and serotonin pathways of tryptophan metabolism and the etiology and pathophysiology of depression. Stress 11, 198–209. 10.1080/10253890701754068 Mooy J. M., de Vries H., Grootenhuis P. A., Bouter L. M., Heine R. J. (2000). Major stressful life events in relation to prevalence of undetected type 2 diabetes: the Hoorn Study. Diabetes Care 23, 197–201. 10.2337/diacare.23.2.197 Morand E. F., Leech M. (1999). Glucocorticoid regulation of inflammation: the plot thickens. Inflamm. Res. 48, 557–560. 10.1007/s000110050503 Mulder A. H., Tack C. J., Olthaar A. J., Smits P., Sweep F. C. G. J., Bosch R. R. (2005). Adrenergic receptor stimulation attenuates insulin-stimulated glucose uptake in 3T3–L1 adipocytes by inhibiting GLUT4 translocation. Am. J. Physiol. Endocrinol. Metab. 289, E627–E633. 10.1152/ajpendo.00079.2004 Munhoz C. D., García-Bueno B., Madrigal J. L. M., Lepsch L. B., Scavone C., Leza J. C. (2008). Stress-induced neuroinflammation: mechanisms and new pharmacological targets. Braz. J. Med. Biol. Res. 41, 1037–1046. 10.1590/s0100-879x2008001200001 Musso G., Gambino R., Pacini G., De Michieli F., Cassader M. (2009). Prolonged saturated fat-induced, glucose-dependent insulinotropic polypeptide elevation is associated with adipokine imbalance and liver injury in nonalcoholic steatohepatitis: dysregulated enteroadipocyte axis as a novel feature of fatty liver. Am. J. Clin. Nutr. 89, 558–567. 10.3945/ajcn.2008.26720 Nadrowski P., Chudek J., Skrzypek M., Puzianowska-Ku?nicka M., Mossakowska M., Wiecek A., et al.. (2016). Associations between cardiovascular disease risk factors and IL-6 and hsCRP levels in the elderly. Exp. Gerontol. 85, 112–117. 10.1016/j.exger.2016.10.001 Nagatsu T., Sawada M. (2005). Inflammatory process in Parkinson’s disease: role for cytokines. Curr. Pharm. Des. 11, 999–1016. 10.2174/1381612053381620 Nicoll J. A., Mrak R. E., Graham D. I., Stewart J., Wilcock G., MacGowan S., et al.. (2000). Association of interleukin-1 gene polymorphisms with Alzheimer’s disease. Ann. Neurol. 47, 365–368. 10.1002/1531-8249(200003)47:3<365::AID-ANA13>3.3.CO;2-7 Norman G. J., Karelina K., Zhang N., Walton J. C., Morris J. S., Devries A. C. (2010). Stress and IL-1β contribute to the development of depressive-like behavior following peripheral nerve injury. Mol. Psychiatry 15, 404–414. 10.1038/mp.2009.91 Padro C. J., Sanders V. M. (2014). Neuroendocrine regulation of inflammation. Semin. Immunol. 26, 357–368. 10.1016/j.smim.2014.01.003 Park H. J., Lee P. H., Ahn Y. W., Choi Y. J., Lee G., Lee D.-Y., et al.. (2007). Neuroprotective effect of nicotine on dopaminergic neurons by anti-inflammatory action. Eur. J. Neurosci. 26, 79–89. 10.1111/j.1460-9568.2007.05636.x Peng Y.-L., Liu Y.-N., Liu L., Wang X., Jiang C.-L., Wang Y.-X. (2012). Inducible nitric oxide synthase is involved in the modulation of depressive behaviors induced by unpredictable chronic mild stress. J. Neuroinflammation 9:75. 10.1186/1742-2094-9-75 Perez Nievas B. G., Hammerschmidt T., Kummer M. P., Terwel D., Leza J. C., Heneka M. T. (2011). Restraint stress increases neuroinflammation independently of amyloid β levels in amyloid precursor protein/PS1 transgenic mice. J. Neurochem. 116, 43–52. 10.1111/j.1471-4159.2010.07083.x Pérez-Nievas B. G., García-Bueno B., Caso J. R., Menchén L., Leza J. C. (2007). Corticosterone as a marker of susceptibility to oxidative/nitrosative cerebral damage after stress exposure in rats. Psychoneuroendocrinology 32, 703–711. 10.1016/j.psyneuen.2007.04.011 Perry V. H., Cunningham C., Holmes C. (2007). Systemic infections and inflammation affect chronic neurodegeneration. Nat. Rev. Immunol. 7, 161–167. 10.1038/nri2015 Pierce B. L., Ballard-Barbash R., Bernstein L., Baumgartner R. N., Neuhouser M. L., Wener M. H., et al.. (2009). Elevated biomarkers of inflammation are associated with reduced survival among breast cancer patients. J. Clin. Oncol. 27, 3437–3444. 10.1200/JCO.2008.18.9068 Qin J., Jin F., Li N., Guan H., Lan L., Ni H., et al.. (2015). Adrenergic receptor β2 activation by stress promotes breast cancer progression through macrophages M2 polarization in tumor microenvironment. BMB Rep. 48, 295–300. 10.5483/bmbrep.2015.48.5.008 Quan N., Banks W. A. (2007). Brain-immune communication pathways. Brain Behav. Immun. 21, 727–735. 10.1016/j.bbi.2007.05.005 Raison C. L., Borisov A. S., Woolwine B. J., Massung B., Vogt G., Miller A. H. (2010). Interferon-α effects on diurnal hypothalamic–pituitary–adrenal axis activity: relationship with proinflammatory cytokines and behavior. Mol. Psychiatry 15, 535–547. 10.1038/mp.2008.58 Rich-Edwards J. W., Mason S., Rexrode K., Spiegelman D., Hibert E., Kawachi I., et al.. (2012). Physical and sexual abuse in childhood as predictors of early-onset cardiovascular events in women. Circulation 126, 920–927. 10.1161/CIRCULATIONAHA.111.076877 Ridker P. M., Rifai N., Rose L., Buring J. E., Cook N. R. (2002). Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N. Engl. J. Med. 347, 1557–1565. 10.1056/nejmoa021993 Rohleder N. (2014). Stimulation of systemic low-grade inflammation by psychosocial stress. Psychosom. Med. 76, 181–189. 10.1097/PSY.0000000000000049 Rose-John S. (2012). IL-6 trans-signaling via the soluble IL-6 receptor: importance for the pro-inflammatory activities of IL-6. Int. J. Biol. Sci. 8, 1237–1247. 10.7150/ijbs.4989 Rosenzweig S., Reibel D. K., Greeson J. M., Edman J. S., Jasser S. A., McMearty K. D., et al.. (2007). Mindfulness-based stress reduction is associated with improved glycemic control in type 2 diabetes mellitus: a pilot study. Altern. Ther. Health Med. 13, 36–38. Salgado R., Junius S., Benoy I., Van Dam P., Vermeulen P., Van Marck E., et al.. (2003). Circulating interleukin-6 predicts survival in patients with metastatic breast cancer. Int. J. Cancer 103, 642–646. 10.1002/ijc.10833 Schroder K., Tschopp J. (2010). The inflammasomes. Cell 140, 821–832. 10.1016/j.cell.2010.01.040 Scrivo R., Vasile M., Bartosiewicz I., Valesini G. (2011). Inflammation as “common soil” of the multifactorial diseases. Autoimmun. Rev. 10, 369–374. 10.1016/j.autrev.2010.12.006 Seidman M. D., Standring R. T. (2010). Noise and quality of life. Int. J. Environ. Res. Public Health 7, 3730–3738. 10.3390/ijerph7103730 Smith R. S. (1991). The macrophage theory of depression. Med. Hypotheses 35, 298–306. 10.1016/0306-9877(91)90266-2 Sorrells S. F., Caso J. R., Munhoz C. D., Sapolsky R. M. (2009). The stressed CNS: when glucocorticoids aggravate inflammation. Neuron 64, 33–39. 10.1016/j.neuron.2009.09.032 Steptoe A., Hamer M., Chida Y. (2007). The effects of acute psychological stress on circulating inflammatory factors in humans: a review and meta-analysis. Brain Behav. Immun. 21, 901–912. 10.1016/j.bbi.2007.03.011 Sterling P., Eyer J. (1988). “Allostasis: a new paradigm to explain arousal pathology,” in Handbook of Life Stress, Cognition and Health, eds Fisher S., Reason J. (Oxford: John Wiley & Sons; ), 629–649. Su S., Jimenez M. P., Roberts C. T. F., Loucks E. B. (2015). The role of adverse childhood experiences in cardiovascular disease risk: a review with emphasis on plausible mechanisms. Curr. Cardiol. Rep. 17:88. 10.1007/s11886-015-0645-1 Szczepanska-Sadowska E., Cudnoch-Jedrzejewska A., Ufnal M., Zera T. (2010). Brain and cardiovascular diseases: common neurogenic background of cardiovascular, metabolic and inflammatory diseases. J. Physiol. Pharmacol. 61, 509–521. Tack C. J., Stienstra R., Joosten L. A. B., Netea M. G. (2012). Inflammation links excess fat to insulin resistance: the role of the interleukin-1 family. Immunol. Rev. 249, 239–252. 10.1111/j.1600-065X.2012.01145.x Thaker P. H., Han L. Y., Kamat A. A., Arevalo J. M., Takahashi R., Lu C., et al.. (2006). Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nat. Med. 12, 939–944. 10.1038/nm1447 Theron A. J., Steel H. C., Tintinger G. R., Feldman C., Anderson R. (2013). Can the anti-inflammatory activities of β2-agonists be harnessed in the clinical setting? Drug Des. Devel. Ther. 7, 1387–1398. 10.2147/DDDT.S50995 Thiem S., Pierce T. P., Palmieri M., Putoczki T. L., Buchert M., Preaudet A., et al.. (2013). mTORC1 inhibition restricts inflammation-associated gastrointestinal tumorigenesis in mice. J. Clin. Invest. 123, 767–781. 10.1172/JCI65086 Thurston R. C., Chang Y., Derby C. A., Bromberger J. T., Harlow S. D., Janssen I., et al.. (2014). Abuse and subclinical cardiovascular disease among midlife women: the study of women’s health across the nation. Stroke 45, 2246–2251. 10.1161/STROKEAHA.114.005928 Tilg H., Moschen A. R. (2011). IL-1 cytokine family members and NAFLD: neglected in metabolic liver inflammation. J. Hepatol. 55, 960–962. 10.1016/j.jhep.2011.04.007 Tsirpanlis G. (2005). Inflammation in atherosclerosis and other conditions: a response to danger. Kidney Blood Press. Res. 28, 211–217. 10.1159/000087121 Tsukuda K., Mogi M., Iwanami J., Min L.-J., Sakata A., Jing F., et al.. (2009). Cognitive deficit in amyloid-β-injected mice was improved by pretreatment with a low dose of telmisartan partly because of peroxisome proliferator-activated receptor-γ activation. Hypertension 54, 782–787. 10.1161/HYPERTENSIONAHA.109.136879 Tsuneki H., Tokai E., Sugawara C., Wada T., Sakurai T., Sasaoka T. (2013). Hypothalamic orexin prevents hepatic insulin resistance induced by social defeat stress in mice. Neuropeptides 47, 213–219. 10.1016/j.npep.2013.02.002 von K?nel R., Bellingrath S., Kudielka B. M. (2008). Association between burnout and circulating levels of pro- and anti-inflammatory cytokines in schoolteachers. J. Psychosom. Res. 65, 51–59. 10.1016/j.jpsychores.2008.02.007 Weber M. D., Frank M. G., Tracey K. J., Watkins L. R., Maier S. F. (2015). Stress induces the danger-associated molecular pattern HMGB-1 in the hippocampus of male Sprague Dawley rats: a priming stimulus of microglia and the NLRP3 inflammasome. J. Neurosci. 35, 316–324. 10.1523/JNEUROSCI.3561-14.2015 Wellen K. E., Hotamisligil G. S. (2005). Inflammation, stress, and diabetes. J. Clin. Invest. 115, 1111–1119. 10.1172/jci25102 Wohleb E. S., Delpech J.-C. (2016). Dynamic cross-talk between microglia and peripheral monocytes underlies stress-induced neuroinflammation and behavioral consequences. Prog. Neuropsychopharmacol. Biol. Psychiatry [Epub ahead of print]. 10.1016/j.pnpbp.2016.04.013 Wong M.-L., Inserra A., Lewis M. D., Mastronardi C. A., Leong L., Choo J., et al.. (2016). Inflammasome signaling affects anxiety- and depressive-like behavior and gut microbiome composition. Mol. Psychiatry 21, 797–805. 10.1038/mp.2016.46 Wyss-Coray T. (2006). Inflammation in Alzheimer disease: driving force, bystander or beneficial response? Nat. Med. 12, 1005–1015. 10.1038/nm1484 Zhang Y., Liu L., Peng Y.-L., Liu Y.-Z., Wu T.-Y., Shen X.-L., et al.. (2014). Involvement of inflammasome activation in lipopolysaccharide-induced mice depressive-like behaviors. CNS Neurosci. Ther. 20, 119–124. 10.1111/cns.12170 Zhao L., Xu J., Liang F., Li A., Zhang Y., Sun J. (2015). Effect of chronic psychological stress on liver metastasis of colon cancer in mice. PLoS One 10:e0139978. 10.1371/journal.pone.0139978 Zhou J.-R., Xu Z., Jiang C.-L. (2008). Neuropeptide Y promotes TGF-β1 production in RAW264.7 cells by activating PI3K pathway via Y1 receptor. Neurosci. Bull. 24, 155–159. 10.1007/s12264-008-0130-6 Zhou J.-R., Zhang L.-D., Wei H.-F., Wang X., Ni H.-L., Yang F., et al.. (2013). Neuropeptide Y induces secretion of high-mobility group box 1 protein in mouse macrophage via PKC/ERK dependent pathway. J. Neuroimmunol. 260, 55–59. 10.1016/j.jneuroim.2013.04.005 Zhu C.-B., Blakely R. D., Hewlett W. A. (2006). The proinflammatory cytokines interleukin-1β and tumor necrosis factor-α activate serotonin transporters. Neuropsychopharmacology 31, 2121–2131. 10.1038/sj.npp.1301029
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