Involvement of inflammatory cytokines in central nervous system injury

Pro-inflammatory cytokines, interleukin (IL) 1 and tumor necrosis factor (TNF), possess a wide range of biological actions in various tissues. In recent years, there has been increasing evidence that these cytokines are involved in inflammatory reactions in central nervous system (CNS) diseases. Although many studies have demonstrated that IL-1, TNF, and their mRNA are up-regulated in the CNS after injury, the functional roles of these cytokines in the injury are far from completely understood. Overexpression of these cytokines, such as observed during the early stage of injury, can be harmful for the injured tissue. However, low levels of these cytokines, observed during the recovery stage after injury, can enhance repair processes of the injured tissues.     

外周血炎性细胞因子与类风湿关节炎

背景：由滑膜细胞、单核/巨噬细胞以及淋巴细胞等产生的炎性细胞因子在类风湿关节炎的发病中发挥着重要作用。白细胞介素17 是近年来发现的一个炎性细胞因子,与很多自身免疫性疾病有关。 目的：观察类风湿关节炎患者血清中辅助性T细胞17相关的白细胞介素17水平及其与红细胞沉降率、C-反应蛋白、疾病活动性的相关性。 方法：纳入2008年1月至2009年12月在解放军成都军区总医院就诊的符合1987年美国风湿病协会修订的类风湿关节炎分类标准的类风湿关节炎患者79例作为病例组,同时选取同时期性别、年龄与病例组相匹配的50名健康体检者作为对照组。根据28处关节疾病活动性评分指数将病例组分为活动组49例和稳定组30例。 结果与结论：ELISA检测结果显示,类风湿关节炎患者血清白细胞介素17水平明显高于对照组(P < 0.01),且活动期患者的白细胞介素17水平高于稳定期患者(P < 0.01)。Pearson相关分析结果显示,活动期类风湿关节炎患者血清中白细胞介素17水平与红细胞沉降率、C-反应蛋白、28处关节疾病活动性评分指数均呈正相关(r=0.459,0.379,0.455;P < 0.05)。说明白细胞介素17参与了类风湿关节炎的炎症反应,与红细胞沉降率、C-反应蛋白、28处关节疾病活动性评分指数等同样能反映病情的活动性。     

Drospirenone increases central and peripheral beta-endorphin in ovariectomized female rats

OBJECTIVE: Drospirenone is the unique progestin derived from 17-spironolactone used for contraception and hormone therapy. Few data are available concerning the effects of drospirenone on the central nervous system and neuroendocrine milieu. The opioid beta-endorphin and the neurosteroid allopregnanolone are considered markers of neuroendocrine functions, and their synthesis and activity are regulated by gonadal steroids. The aim of the present study was to evaluate the effect of a 2-week oral treatment with drospirenone, estradiol valerate, and combined therapy of drospirenone + estradiol valerate on central and peripheral beta-endorphin and allopregnanolone levels in ovariectomized female rats. DESIGN: Seven groups of Wistar ovariectomized rats received oral drospirenone (0.1, 0.5, and 1.0 mg/kg per day), estradiol valerate (0.05 mg/kg per day), or drospirenone (0.1, 0.5, and 1.0 mg/kg per day) + estradiol valerate (0.05 mg/kg per day). One group of fertile and one group of ovariectomized rats were used as controls. beta-endorphin levels were measured in frontal and parietal lobes, hippocampus, hypothalamus, anterior and neurointermediate pituitary, and plasma, and allopregnanolone content was assessed in frontal and parietal lobes, hippocampus, hypothalamus, anterior pituitary, adrenal glands, and serum. RESULTS: Ovariectomy induced a significant decrease in beta-endorphin and allopregnanolone content in all brain areas analyzed and in circulating levels, whereas it increased allopregnanolone content in the adrenal gland. Estradiol valerate replacement increased beta-endorphin and allopregnanolone levels in all brain areas analyzed and in plasma/serum. Drospirenone treatment significantly increased beta-endorphin levels in all brain areas analyzed (with the only exception being the parietal lobe), whereas it produced no effect on allopregnanolone levels. The addition of drospirenone to estradiol valerate did not modify the effects of estradiol valerate on beta-endorphin or allopregnanolone levels. Drospirenone showed an additive and synergistic effect with estradiol in the neurointermediate lobe on beta-endorphin synthesis. CONCLUSIONS: Drospirenone significantly increases central and circulating beta-endorphin levels and does not seem to interfere with allopregnanolone production.     

Combinatorial signals by inflammatory cytokines and chemokines mediate leukocyte interactions with extracellular matrix

On their extravasation from the vascular system into inflamed tissues, leukocytes must maneuver through a complex insoluble network of molecules termed the extracellular matrix (ECM). Leukocytes navigate toward their target sites by adhering to ECM glycoproteins and secreting degradative enzymes, while constantly orienting themselves in response to specific signals in their surroundings. Cytokines and chemokines are key biological mediators that provide such signals for cell navigation. Although the individual effects of various cytokines have been well characterized, it is becoming increasingly evident that the mixture of cytokines encountered in the ECM provides important combinatorial signals that influence cell behavior. Herein, we present an overview of previous and ongoing studies that have examined how leukocytes integrate signals from different combinations of cytokines that they encounter either simultaneously or sequentially within the ECM, to dynamically alter their navigational activities. For example, we describe our findings that tumor necrosis factor (TNF)-alpha acts as an adhesion-strengthening and stop signal for T cells migrating toward stromal cell-derived factor-1alpha, while transforming growth factor-beta down-regulates TNF-alpha-induced matrix metalloproteinase-9 secretion by monocytes. These findings indicate the importance of how one cytokine, such as TNF-alpha, can transmit diverse signals to different subsets of leukocytes, depending on its combination with other cytokines, its concentration, and its time and sequence of exposure. The combinatorial effects of multiple cytokines thus affect leukocytes in a step-by-step manner, whereby cells react to cytokine signals in their immediate vicinity by altering their adhesiveness, directional movement, and remodeling of the ECM.     

The role of cytokines in inflammatory conditions of the central nervous system

Cytokines, the products of both immune system cells and some endogenous cells of the central nervous system (CNS), contribute significantly to inflammatory and autoimmune conditions within the CNS by inducing major histocompatibility complex antigen expression on endothelial and glial cells. This has the net effect of enhancing the homing to and migration of inflammatory cells across the blood-brain barrier into the CNS and mediating functional and structural changes in CNS elements. Cytokines have been localized in autoimmune and inflammatory lesions within the CNS and their critical role for these processes have been confirmed in experiments on animal models of human immune-mediated CNS disease.     

油酸调节人血管平滑肌细胞TLR4的增殖活性及炎性因子的表达

目的 探讨油酸对人主动脉血管平滑肌细胞TLR4及炎性因子表达的调节作用.方法 MTT法检测细胞增殖活性;实时荧光定量PCR法检测TLR4及炎性因子mRNA的表达;Western blot法检测细胞TLR4蛋白表达,ELISA法检测炎性因子蛋白含量.结果 油酸促进人主动脉血管平滑肌细胞增殖活性,增加油酸浓度,抑制细胞增殖.油酸上调TLR4、IL-6、IL-8和MCP-1 mRNA表达最大幅度为6.5、7.4、7.4和7.1倍.IL-6、IL-8和MCP-1蛋白表达最大上调幅度为2.16、1.93和2.06倍.200 μmol/L组TLR4蛋白表达的吸光度值为(1.70±0.62),与对照组(0.29 ±0.22)比较P＜0.05.LPS组TR4、IL-6、IL-8和MCP-1的表达明显增加(P＜0.05).结论 油酸促进人主动脉血管平滑肌细胞TLR4及炎性因子mRNA及蛋白表达.     

Lymphocyte-derived cytokines in inflammatory arthritis

Inflammatory bone loss is observed in a number of disorders including rheumatoid arthritis (RA), osteoporosis and periodontal disease. Lymphocytes are key components in the onset and exacerbation of autoimmune diseases and the cytokines produced by these cells have a powerful impact on disease progression. Many cytokines implicated in inflammation impact upon osteoclast (OCL) differentiation and function either directly or indirectly by modulating the relative expression of RANKL and OPG. This review highlights the contribution of lymphocyte-derived cytokines to the bone loss observed in RA and other autoimmune disorders. A greater understanding of the cytokines involved in these disorders will ultimately lead to the identification of novel therapeutic strategies for the prevention of bone loss in these diseases.     

Lymphocyte-derived cytokines in inflammatory arthritis

Inflammatory bone loss is observed in a number of disorders including rheumatoid arthritis (RA), osteoporosis and periodontal disease. Lymphocytes are key components in the onset and exacerbation of autoimmune diseases and the cytokines produced by these cells have a powerful impact on disease progression. Many cytokines implicated in inflammation impact upon osteoclast (OCL) differentiation and function either directly or indirectly by modulating the relative expression of RANKL and OPG. This review highlights the contribution of lymphocyte-derived cytokines to the bone loss observed in RA and other autoimmune disorders. A greater understanding of the cytokines involved in these disorders will ultimately lead to the identification of novel therapeutic strategies for the prevention of bone loss in these diseases.     

Age-related inflammatory cytokines and disease

Aging is associated with chronic low-grade increases in circulating levels of inflammatory markers. A wide range of environmental factors, including smoking, infections, and obesity, genetic factors, and the declining function of sex hormones may contribute to systemic low-grade inflammatory activity in older individuals. Age-associated disease may exacerbate this phenomenon. The multifunctional cytokines TNF-alpha and IL-6 have been associated with morbidity and mortality in the elderly. Evidence supports the direct role of TNF-alpha in the pathogeneses of atherosclerosis, type 2 DM, and AD in older individuals. Age-related increases in systemic levels of TNF-alpha could provide a unifying basis for these disorders. Furthermore, TNF-alpha induces a catabolic state that causes frailty. Circulating levels of IL-6 seem to be a strong risk factor for frailty in the elderly, which could reflect its association with increased production of TNF-alpha. IL-6 also may be a risk factor for thromboembolic complications. In healthy, elderly populations, high circulating levels of TNF-alpha and IL-6 predict mortality, independent of comorbidity, indicating that TNF-alpha and IL-6 cause morbidity and mortality. In cohorts of frail, older individuals, TNF-alpha and IL-6 also act as disease markers. Circulating levels of TNF-alpha seem to be the best predictor of mortality in frail, elderly populations with a high mortality rate, whereas IL-6 seems to be the strongest risk marker in healthy, elderly populations. This finding could reflect that in relatively healthy old populations the increase in circulating levels of IL-6 represent a systemic response to local proinflammatory activities; however, when age-related inflammatory diseases progress, levels of TNF-alpha increase in the circulation and become gradually a stronger risk marker than IL-6. In conclusion low-grade elevations in levels of circulating cytokines are strong independent risk factors of morbidity and mortality in the elderly, and lifestyle factors and comorbidities may modulate these levels. Exercise and dietary interventions may be possible strategies to decrease inflammatory activity and improve the health status of the elderly.     

Recent findings on how proinflammatory cytokines cause pain: peripheral mechanisms in inflammatory and neuropathic hyperalgesia

Numerous experimental studies provide evidence that proinflammatory cytokines induce or facilitate inflammatory as well as neuropathic pain and hyperalgesia. Direct receptor-mediated actions of cytokines on afferent nerve fibers have been reported as well as cytokine effects involving further mediators. The final outcome of cytokine action greatly depends on whether they act in the central of in the peripheral nervous system. Here we summarize recent findings on the peripheral mechanisms of action of three prototypic proinflammatory cytokines, interleukin-1beta, interleukin-6 and tumor necrosis factor-alpha, with regards to pain and hyperalgesia.     

慢性肝病患者外周血Ghrelin与炎性细胞因子的水平检测及其相关性研究

目的:探讨外周血Ghrelin与炎性细胞因子TNF-α、IL-1及IL-6表达水平与慢性乙型肝炎、肝炎肝硬化、非酒精性脂肪性肝病肝脏损害程度的相关关系.方法:慢性肝病患者组和健康对照组血浆中Ghrelin、TNF-α、IL-1及IL-6表达水平检测采用酶联免疫吸附实验(ELISA).结果:慢性乙型肝炎、肝炎肝硬化患者外周血Ghrelin表达明显升高,与正常对照组比较差异显著(P＜0.05,P＜0.01),失代偿期肝硬化(B、C级)患者外周血Ghrelin水平明显高于慢性乙型肝炎组(P＜0.05);Ghrelin在非酒精性脂肪肝病患者组外周血明显降低,与正常对照组比较差异显著(P＜0.01);慢性肝炎、肝炎肝硬化患者外周血Ghrelin表达与炎性细胞因子TNF-α、IL-1及IL-6呈正相关(慢性肝炎组r值分别为0.587、0.995、0.985,肝硬化组r值分别为0.730、0.966、0.979),而在NAFLD疾病组则呈负相关(r值分别为-0.660、-0.873、-0.894).结论:Ghrelin在慢性乙型肝炎、肝炎肝硬化患者组外周血高表达,而在非酒精性脂肪性肝病患者组外周血低表达,Ghrelin表达水平与慢性肝病的发生发展过程相关.     

Corticotropin-releasing factor-1 receptors in the basolateral amygdala mediate stress-induced anorexia

Corticotropin-releasing factor (CRF) receptor activation within the basolateral amygdala (BLA) has been relatively unexplored compared with the central nucleus of the amygdala (CeA), despite the fact that CRF receptors are more densely distributed in BLA than in CeA. The authors show that infusion of CRF into BLA, but not CeA, decreases feeding and increases grooming. These effects are mediated by CRF-sub-1 receptors, because they are blocked by intra-BLA treatment with NBI27914 (NBI), a CRF-sub-1 antagonist, but not Astressin 2B, a CRF-sub-2 antagonist. Exposure to a stressor results in behaviors identical to those seen after intra-BLA CRF infusion. These stress-induced changes are prevented by pre-stress treatment with NBI but not Astressin 2B. These data demonstrate that stimulation of intra-BLA CRF-sub-1 receptors is both necessary and sufficient for eliciting stress-induced anorexia and grooming.     

Contribution of peripheral versus central EP1 prostaglandin receptors to inflammatory pain

Few studies on transcranial brain sonography have been performed in hereditary and non-hereditary ataxias. The objective of the present study was to report transcranial brain sonography findings in a sample of clinically and molecularly proven Machado-Joseph disease patients and to compare these data against those of an age- and gender-matched control group. A cross-sectional study on transcranial brain sonography was conducted in 30 Machado-Joseph disease patients. Transcranial brain sonography was performed by an experienced sonographer blinded to the clinical, genetic, and neuroimaging data. The results were compared with those of a control group of 44 healthy subjects matched for age and gender. The sonographic findings were also correlated with clinical features and genetic data in Machado-Joseph disease group. A significantly higher frequency of substantia nigra and lenticular nucleus hyperechogenicity was found in the Machado-Joseph disease group compared to an age- and gender-matched healthy control group (p < 0.001). The substantia nigra echogenic area proved to be the best predictor for differentiating cases from controls. Third and lateral ventricles were significantly larger in the Machado-Joseph disease patients than in the control subjects. No significant correlations were found between transcranial brain sonography findings and Machado-Joseph disease demographic/clinical data. Transcranial brain sonography findings in Machado-Joseph disease patients differed significantly to those in age- and gender-matched controls. Substantia nigra hyperechogenicity occurred frequently in Machado-Joseph disease patients and was found to be the best predictor for differentiating cases from controls. Additionally, this data describes the occurrence of brain atrophy in Machado-Joseph disease group.     

炎症因子与糖尿病肾病关系的研究进展

近年的研究发现糖尿病肾病是一种炎症性疾病。许多炎症因子及前炎症因子如急性时相蛋白、趋化因子、黏附分子、肿瘤坏死因子-α、血浆纤溶酶原激活物抑制因子、白细胞介素等与糖尿病肾病发生发展密切相关。研究炎症因子及其受体调节和信号转导通路机制可能为糖尿病肾病的治疗提供全新的理论基础，同时也为临床提供新的更为有效的诊治手段。     

T cells specific for the myelin oligodendrocyte glycoprotein mediate an unusual autoimmune inflammatory response in the central nervous system

Myelin oligodendrocyte glycoprotein (MOG)-specific T cells mediate an autoimmune inflammatory response in the central nervous system (CNS) that differs radically from conventional models of T cell-mediated experimental allergic encephalomyelitis (EAE). Using synthetic peptides an encephalitogenic T cell epitope of MOG for the Lewis rat was identified within the extracellular IgG V-like domain of the protein, amino acids 44-53 (FSRVVHLYRN).The adoptive transfer of CD4⁺ T cells specific for this epitope induce an intense, dose-dependent inflammatory response in the CNS of naive syngeneic recipients. However, unlike the inflammatory response induced by myelin basic protein (MBP)-specific T cell lines, inflammation mediated by the MOG peptide-specific T cells failed to induce a gross neurological deficit. This unexpected observation was not due to a reduction in the overall inflammatory response in the CNS, but was specifically associated with a decrease in the extent of parenchymal (as opposed to perivascular) inflammation, a selective decrease in the number of ED1⁺ macrophages infiltrating the CNS, and a total lack of peripheral nerve inflammation. The decreased recruitment of macrophages into the CNS could not be ascribed to deficiences in the synthesis of interferon-γ, tumor necrosis factor-a, interleukin (IL)-6 or IL-2 by the T cell line. Moreover, this sub-clinical inflammatory response induced severe blood-brain barrier dysfunction as demonstrated by the induction of severe clinical disease following intravenous injection of a demyelinating MOG-specific monoclonal antibody. The neurological deficit in EAE thus exhibits an unexpected dependence on the identity of the target autoantigen, which determines the extent and nature of the local inflammatory response and ultimately the extent of the neurological deficit.