突触细胞黏附分子在应激中作用的研究进展

突触细胞黏附分子是一类介导突触前、后膜结构和功能互作的膜表面糖蛋白,可以动态调节突触活动和可塑性,其表达与功能受到环境因素调控。突触细胞黏附分子亦是应激反应重要的效应分子之一,可介导应激对认知和情绪的不良影响。本文综述近年来突触细胞黏附分子在应激中作用的研究进展,旨在为应激相关障碍的分子机制研究和药物研发提供思路。     

应激对免疫功能的影响

应激(stress)可产生广泛的、复杂的生物学效应,如神经内分泌系统功能的改变、心血、管反应,以及心理和行为方面的变化等。长期在应激状态下生活可导致机体抗病能力下降,从而产生多种疾病,这可能是机体免疫功能下降的一种反映。近年来已有许多学者报道应激可通过神经内分泌系统的作用影响机体的免疫功能。一、应激与疾病的关系应激对于多种疾病的发病、演变以至结局都有密切的关系,这是由于应激可使机体产生复杂的生理和心理反应。关于机体在应激过程中所表现出的各种反应机制,众说不一,早期     

P小体的研究进展

P小体(processing bodies)即mRNA处理小体,它是一种富含了多种功能相关蛋白以及RNA的胞浆集合体(cytoplasmic foci)。研究表明这种胞浆结构与mRNA的降解过程以及RNA干扰介导的转录后基因沉默效应有关,另外,它还参与了细胞增殖和细胞周期以及宿主的抗病毒感染能力的调控。     

巨噬细胞凋亡及其调控

巨噬细胞通过介导和调控自身及其他细胞凋亡而实现其免疫调节和效应细胞功能.引起巨噬细胞凋亡的原因有生物、化学、病理、自身等因素.不仅巨噬细胞自身凋亡和凋亡调控有其特点,更为有趣的是,巨噬细胞可根据需要：介导或抑制自身凋亡;介导或抑制其他细胞凋亡;抑制自身凋亡,介导其他细胞凋亡.这可能是巨噬细胞在免疫调节,特别是肿瘤免疫中发挥重要作用的基础.     

大豆提取物（CKBN）对免疫低下小鼠免疫功能的影响

目的观察大豆提取物（CKBN）对免疫低下小鼠免疫功能的影响。方法腹腔注射环磷酰胺（cyclophosphamide,CTX）建立免疫功能低下小鼠模型,观察1、25、50、100 mg/kg剂量CKBN对免疫低下小鼠免疫功能的影响。结果25 mg/kg组的CKBN可显著增加免疫低下小鼠的脾指数;25、50、100 mg/kg组均能明显抑制环磷酰胺对小鼠外周血白细胞数量的影响,1 mg/kg组可显著提高单核细胞百分率,50 mg/kg组可显著提高中性粒细胞百分率;100 mg/kg组的IgG2a水平高于环磷酰胺组;1、25、50 mg/kg可显著提高腹腔巨噬细胞的吞噬功能;25 mg/kg组可显著提高NK细胞杀伤活性。结论CKBN能显著增强CTX造成的免疫低下小鼠的免疫功能。     

选择性内质网自噬受体研究进展

内质网自噬是一种可以清除受损内质网的选择性自噬,其主要功能是参与内质网容量和质量的控制,维持细胞稳态。选择性内质网自噬由相关的受体蛋白介导,这些蛋白在疾病发生发展中可能起到重要靶点效应。本文对选择性内质网自噬的作用及其与疾病的关系加以综述,并且归纳总结了相关受体蛋白介导内质网自噬的研究进展,以期对研究内质网自噬相关疾病的发生机制、发展过程及其防治手段提供新的思路和切入点。     

珍奥酵母核酸对环磷酰胺致小鼠免疫功能低下的影响

目的 通过环磷酰胺致小鼠免疫功能低下,建立BALB/C小鼠免疫功能低下模型,评价珍奥酵母核酸对小鼠免疫功能低下的作用.方法 选用BALB/C小鼠,随机分组,分别给予相应的处理,选择T淋巴细胞亚群CD69+/CD3+比值、NK细胞亚群CD69+/NKG2D+比值、淋巴细胞转化率及血清IL-2含量作为细胞免疫的指标.结果 核酸各剂量组和添加剂组均可使免疫低下小鼠外周血和脾的T淋巴细胞亚群CD69+/CD3+比值、NK细胞亚群CD69+/NKG2D+比值提高,同时可提高免疫低下小鼠淋巴细胞转化率及IL-2水平,尤以高、中剂量核酸组和添加剂组明显(P＜0.05).结论 珍奥酵母核酸可以提高免疫低下小鼠的免疫功能,以其为珍奥酵母核酸的临床应用及提高机体免疫力提供了实验依据.     

Th17/Treg细胞失衡与子宫颈癌

Th17细胞是近年发现的一种新型CD4^＋效应性T细胞,以其特异性的分泌IL-17而命名。介导免疫耐受的Treg细胞和介导炎症反应的Th17细胞间功能和分化过程相互对抗,在正常状态下,两者保持平衡,但机体发生功能异常时常表现出Treg/Th17失衡,引起炎性反应、自身免疫性疾病、移植物抗宿主病等的发生和发展,并决定疾病的转归和预后,在肿瘤免疫中亦发挥了重要作用。该文就Treg/Th17失衡在肿瘤,尤其是子宫颈癌发生发展中的作用进行综述。     

水解南珠片对免疫低下小鼠免疫功能的影响

本实验以腹腔注射环磷酰胺建立免疫低下小鼠模型,灌胃给予水解南珠片高、中和低剂量(2.04 g/kg,1.02 g/kg和0.51 g/kg)30 d,观察水解南珠片对免疫低下小鼠免疫功能的影响。结果显示,水解南珠片高剂量(2.04 g/kg)能显著提高免疫低下小鼠单核巨噬细胞系统碳粒廓清指数K(p0.05);水解南珠片高、中、低剂量(2.04 g/kg,1.02 g/kg,0.51 g/kg)能显著提高免疫低下小鼠外周血T淋巴细胞相对数量(p0.01);水解南珠片高、中剂量(2.04 g/kg,1.02 g/kg)能显著提高免疫低下小鼠血清溶血素吸光度值(p0.01)。上述结果表明,水解南珠片对免疫功能低下小鼠的固有免疫、细胞免疫和体液免疫功能均有一定的增强作用。     

铜绿假单胞菌群体感应信号分子PQS的功能多样性研究进展

铜绿假单胞菌(Pseudomonas aeruginosa)是一种革兰氏阴性条件致病菌,可对免疫功能低下或损伤的患者造成持续性感染。铜绿假单胞菌能成功感染离不开其自身产生的毒力因子,而这些毒力因子大多数都受群体感应系统(quorum sensing,QS)调控。铜绿假单胞菌有4个QS系统,分别为las系统、rhl系统、pqs系统和iqs系统。2-庚基-3-羟基-4-喹诺酮(Pseudomonas quinolone signal,PQS)作为铜绿假单胞菌pqs系统的信号分子,不仅能够调控许多毒力因子的表达,也能够影响一些微生物和宿主的多种生理过程。本文总结了PQS多种生物学功能,如介导QS系统、调控生物被膜形成、介导外膜囊泡产生及铁摄取、调节宿主免疫活性、介导细胞毒性作用,以及提供种群保护等。本文旨在突出铜绿假单胞菌PQS的功能多样性,并为PQS新功能研究和抗菌药物的研发提供指导。     

Immunosuppression induced by central action of morphine is not blocked by mifepristone (RU 486)

Morphine causes immunosuppression by binding to opioid receptors on immune cells, or indirectly by acting on receptors in the brain. However, morphine exact mechanism of action has not been elucidated. In the present study, we investigated the role of glucocorticoids in morphine-mediated immunosuppression after acute action in the rat mesencephalon periaqueductal gray (PAG). Natural killer (NK) cell activity and T cell proliferation were used to evaluate potential indirect mechanisms of morphine action. Microinjection of morphine in the ventral-caudal aspect of the PAG significantly (p < 0.01) suppressed splenic NK cell cytotoxic activity (32% reduction), and antiTCR-, IL-2-, antiTCR + IL-2, and Con A-induced thymic (30% to 50% reduction) and splenic (35% to 70% reduction) lymphocyte proliferation compared with PAG-injected saline control animals. The glucocorticoid receptor antagonist mifepristone (RU 486) did not block the immunosuppressive effects of morphine, suggesting that such effects are independent of activation of the hypothalamic-pituitary-adrenal axis.     

Effects of endogenous and exogenous opioids on splenic natural killer cell activity

Previous work from our own and other laboratories has shown that electroshock-induced neurohormonal changes in rodents could modify host-tumor interactions by both increasing the frequency and growth rate of transplanted tumors and decreasing the elimination rate of a radiolabelled natural killer (NK) cell sensitive tumor. To test whether such neurohormonal changes could affect NK activity we subjected mice to tail electrode shock (TES) and examined in vitro splenic NK activity. We found that between 30 and 60 min after TES there is a significant but transient suppression of their splenic NK activity. To determine whether TES-induced endogenous opioids might be involved in this suppression mice were given intraperitoneal injections of the opioid antagonists naloxone or naltrexone before or at the end of the TES session. These drugs prevented NK suppression. In a further test of the hypothesis that opioids alter NK activity mice were given a single intraperitoneal injection of morphine or [D-Ala2-Met5]-beta-endorphin, a relatively stable analogue of beta-endorphin, an endogenous opioid. Contrary to expectations these opioids enhanced splenic NK activity. Our interpretation of these results is that shock-induced NK suppression may not be mediated by endogenous opioids and that the effects of naloxone and naltrexone on NK activity may not be related to their opioid antagonist properties. On the contrary, opioids may participate in a homeostatic rebound from suppression mediated by other neurohormonal mechanisms activated during TES.     

Role of endogenous opioids and histamine in morphine induced emesis

The role of opioid and histaminergic system in morphine induced emesis was investigated in dogs. Morphine (25 micrograms, icv) consistently evoked emesis with an average latency of 195 +/- 29 sec which was fully accounted for by an action on the chemoreceptor trigger zone (CTZ) as its ablation rendered animals refractory to vomiting. Intraventricular pretreatment with opioid antagonist naloxone, histamine H1 antagonist mepyramine and H2 antagonists metiamide and cimetidine afforded protection to icv morphine emesis. The CSF histamine concentration was significantly raised 5 min after icv morphine administration. The results suggest that both endogenous opioid and histamine are involved in morphine emesis. Naloxone in high doses (1600 micrograms, icv) elicited emesis which was not blocked by CTZ ablation confirming our earlier report.     

Effect of anti-human pan-T monoclonal antibodies on lymphocyte proliferative and cytotoxic functions

Effects of anti-human pan-T-specific monoclonal antibodies of the Second International Workshop on Human Leucocyte Differentiation Antigens were investigated in a number of lymphocyte functional tests. Monoclonal antibodies blocking antibody-dependent cytotoxicity (ADCC), PWM-induced IL-2 release, or Con A- and PWM-induced lymphocyte proliferation were found among anti-CD2 and CD3 reagents. Inhibition of lectin-dependent cellular cytotoxicity (LDCC) was found as an exclusive effect of anti-CD2 (the sheep red cell receptor) antibodies. Several anti-CD2s blocked natural killer (NK) activity and/or PWM-induced interferon production. These two effects were exerted by antibodies against epitopes on resting T cells but not by those directed to activation epitopes. The inhibitory activity of individual antibodies in the LDCC and NK tests showed a good correlation. Also, PHA-mediated cytotoxicity (LDCC) and proliferation were in good correlation. Concerning anti-CD3 (T3) reagents, some effects were characteristic for the majority of the antibodies in this group. Namely, induction of proliferation, enhancement of IL-2-dependent cell division, IL-2 consumption by antibody-triggered cells, inhibition of mitogen-induced proliferation but not IL-2 and interferon production were observed. None of the CD3-specific reagents exerted all of these effects. In general, no correlation of the effects with immunoglobulin subclass or CD3 subcluster specificity could be found. Further epitope analysis and affinity data may be required to understand the basis of heterogeneity in functional effects of monoclonal antibodies to the CD3 molecule.     

Endorphins stimulate normal human peripheral blood lymphocyte natural killer activity

Opioid peptides are present in peripheral blood, and may bind to human lymphocytes. In order to determine their influence on human lymphocytes we studied the effect of endogenous opioid peptides on human lymphocyte natural killer function. Beta-endorphin and several analogues (i.e., gamma-endorphin) are shown to enhance human peripheral blood natural killer function. The enhancement of natural killing by these opioid peptides was dose-dependent and naloxone (an opiate antagonist) reversible. In studying various analogues of beta-endorphin, beta-lipotropin and gamma-endorphin were approximately 3-5 times more effective at enhancing peripheral blood NK function than Leu-enkephalin and -endorphin. In addition, we observed that naloxone reversed human fibroblast interferon mediated enhancement of human blood lymphocyte natural killer function. These observations suggest that circulating endogenous opioid peptides may have a physiologic role in regulating human blood lymphocyte natural killing.     

Synergistic proliferation and activation of natural killer cells by interleukin 12 and interleukin 18.

We investigated the effects of IL-12 and IL-18 on unstimulated murine splenocytes and observed that the two cytokines strongly synergized for their proliferation, whereas IL-12 and IL-18 alone were essentially inactive in this respect. Phenotypical and functional analyses of cells proliferating in response to IL-12 and IL-18 revealed that large granular Ly-49C(+)DX5(+)CD3(-)NK blasts were expanded in these cultures and that they displayed cytotoxic activity against Yac-1 cells, a murine NK cell target. Further analyses indicated three major differences between NK cells appearing in response to IL-12 and IL-18 and those derived in the presence of other NK cell growth factors, such as IL-2 or IL-15. First, a population of T-NK cells, i.e. expressing T cell (TCRalphabeta, CD3) and NK cell (Ly-49) markers, was detected amongst cells growing in IL-2 or IL-15 but not in cultures supplemented with IL-12 and IL-18. Second, most NK cells derived with IL-2 or IL-15 expressed the NK1.1 antigen, while those derived with IL-12 and IL-18 did not. Finally, striking differences were observed regarding cytokine production. Cells stimulated with IL-12 and IL-18 in combination, but not with IL-2 or IL-15, produced IFN-gamma, IL-3, IL-6 and TNF. IFN-gamma was not involved in the response of NK cells to IL-12 and IL-18, as indicated by experiments demonstrating that the combination of the two cytokines displayed similar effects on spleen cells from IFN-gammaR-knock-out mice. Receptor (IL-12Rbeta1, IL-12Rbeta2 and IL-18R) gene expression studies did not indicate that the mechanism underlying the synergy between IL-12 and IL-18 involved reciprocal induction of their receptors. Taken together, our results demonstrate that IL-12 and IL-18 exert striking synergistic activities for NK cell proliferation and activation, distinct from those induced by IL-2 or IL-15.     

Involvement of the opioid system in the central antisecretory action of alpha-2 adrenoceptor agonists in rat

The aim of the present study was to analyse the role of the central alpha-2 adrenoceptors in the regulation of gastric acid secretion in pylorus ligated rats. It was found that the intracerebroventricularly (icv.) injected presynaptic alpha-2 adrenoceptor agonist clonidine and the alpha-2A adrenoceptor subtype selective stimulant oxymetazoline exerted a dose dependent inhibition on gastric acid secretion. The antisecretory ED(50) values for clonidine and oxymetazoline were 20 and 7.5 nmol/rat icv., respectively. The antisecretory effect of these compounds was antagonised by the presynaptic adrenoceptor antagonist yohimbine (50 nmol/rat icv.) indicating that the action is mediated through central presynaptic alpha-2 adrenoceptors. Moreover, naloxone (50 nmol/rat icv.)--non-selective opioid antagonist--and naltrindole (0.5 nmol/rat icv.)--delta-opioid receptor selective antagonist--also decreased the antisecretory effect of clonidine and oxymetazoline suggesting that the endogenous opioid system is likely to be involved in the central antisecretory action of alpha-2 adrenoceptor stimulants.     

Glutathione modulates activation-dependent proliferation of human peripheral blood lymphocyte populations without regulating their activated function

L-Buthionine-(S,R)-sulfoximine (BSO) specifically depletes GSH synthesis by inactivating gamma-glutamylcysteine synthetase, whereas 2-ME augments intracellular GSH concentration. These reagents were used to examine GSH regulation of the proliferation and function of human PBL in response to IL-2 or OKT-3 mAb directed at the CD3 T cell Ag. 2-ME enhanced both IL-2-induced proliferation of PBL and CD3- large granular lymphocytes (LGL) and OKT-3 mAb-induced proliferation of CD3+ T cells. BSO partially suppressed activation-induced proliferation in CD3- LGL and CD3+ T cells and totally inhibited the positive co-proliferative regulation by 2-ME in these cells. By contrast, neither BSO nor 2-ME appeared to affect the activation-dependent differentiation of cytotoxic lymphocytes. The absence of effect of 2-ME or BSO on activation-induced PBL NK activity and T cell cytotoxic potential was supported by their negligible effect on the induction of two different markers of activated cytotoxic lymphocytes, namely pore-forming protein gene expression and benzoyloxycarbonyl-1-L-lysine thiobenzylester-esterase activity. BSO inhibition of CD3- LGL proliferation accounted for the inhibitory effects of BSO on both IFN-gamma production in IL-2-stimulated PBL cultures and IL-2-induced PBL lymphokine activated killer activity. The modulatory effects of 2-ME and BSO on lymphocyte proliferation regardless of phenotype (LGL vs T cell) or stimulation (IL-2, via CD3, lectin, etc.) and the functional differentiation of cytotoxic lymphocytes independent of proliferation suggests that these cells share a common site of GSH regulation close to or at the level of DNA synthesis.     

In vivo bidirectional regulation of mouse natural killer (NK) cell cytotoxic activities by Leu-enkephalin: reversibility by naloxone.

Intraperitoneal injection of Leu-enkephalin (LENK, 10 or 7.5 mg/kg) induced bidirectional modulation of natural cytotoxic activities in spleens of CBA mice (suppression followed by enhancement). NK-cytotoxic activity was more affected than the ADCC. Early suppression of NK activity could be reversed by 4 x M excess of naloxone injected 20 min before LENK, suggesting that the suppression was mediated by opioid receptors. Subsequent increase of NK activity could not be abrogated by naloxone, at least not completely. Naloxone itself decreased NK activity 12 hours after treatment, but enhanced ADCC at 24 and 48 hours. This increase was abrogated by LENK. In addition to functional alterations, LENK also induced phenotypic changes of spleen cells, i.e. a decrease in the percentage of asialo-GM-1+ cells 24 hours posttreatment. There was no correlation between LENK-induced alterations of cytotoxic function and the percentage of cells with NK phenotype (GM-1+). Thus, LENK modulates cytolytic functions and the phenotype of NK cells in vivo in a complex way, which besides opioid mechanisms may also include non-opioid ones.