Advances in neuroimmunology最新文献

There is now an impressive range of evidence supporting the important role of cytokines in sleep regulation (see Krueger et al., 1995; De Simoni et al., 1995). It has also been reported that inhibition of nitric oxide (NO) synthesis suppresses sleep in rabbits (Kapás et al., 1994). This is not surprising, since NO is closely involved in neurotransmission (Garthwaite, 1991; Schuman and Madison, 1994) and cytokines are the major inducers of NO synthesis (Hibbs et al., 1990). Further, it is now clear that NO plays an important role in modulating immune responses, possibly through the differential regulation of cytokine synthesis (Taylor-Robinson et al., 1994). In this article, I will provide evidence for the interactions between cytokines and nitric oxide, and discuss their implications in the regulation of immune responses. I shall illustrate these mainly with results from my coworkers and I, from our laboratory rather than attempting an exhaustive review of the subject.

The vascular endothelium is a significant site of NO release that inhibits cellular adhesion and maintains a non-thrombogenic surface. Use of newly described technology suggests for the first time that the maximal release of NO induced by cNOS and iNOS activation may be quite similar, implying that it is the duration of NO release and not the concentration of NO produced from stimulated endothelial cells that accounts for the different biological activities of the enzymes. The respective roles of cNOS and iNOS must be carefully evaluated since both enzymes may have potent biological effects at local sites of production.

This review article summarizes the major findings about the interactions of human sleep structure and the hypothalamo-pituitary-adrenocortical (HPA) system under physiological and pathophysiological conditions, including studies that probe the sleep effects of systemically administered HPA hormones.

Human sleep is regulated by a concerted action of various signal compounds acting at sleep-generating neurons whose central organization is not yet fully understood. During nocturnal sleep the endocrine system is remarkably active, the longest established finding being that growth hormone (GH) release is associated with the initiation of sleep and that there is a steep morning rise of cortisol (Weitzman et al., 1966; Takahashi et al., 1968). Moreover, the effects of exogenously administered corticosteroids and of their excessive endogenous release (e.g. Cushing's disease) were recognized more than 20 years ago.

Fatal Familial Insomnia (FFI) is an autosomal dominant prion disease, characterized by prominent degeneration of the thalamus and involving impaired control of the sleep-wake cycle and of autonomic and endocrine functions. Profound alterations in the sleep-wake cycle consist of progressive decrease or complete absence of sleep activity and loss of any intrinsic cyclic organization of residual sleep. Unbalanced sympathergic activation with preserved parasympathetic drive, associated with chronic secondary hypertension and loss of the physiological nocturnal decrease in blood pressure constitute the characteristic autonomic changes. Neuroendocrine studies document hypercortisolism with abnormal feed-back suppression of adrenocorticotrophic hormone, constantly elevated catecholamine levels and abnormal secretory patterns of growth hormone, prolactin and melatonin. Advanced stages of the disease are invariably characterized by the disappearance of any circadian autonomic and neuroendocrine rhythmicity.

FFI represents a model disease emphasizing the correlations among the different sleep, autonomic and neuroendocrine functions. Clinico-pathological correlations demonstrate the role of the thalamus as an integrative neural structure placed between the limbic system and the hypothalamus and controlling the homeostatic balance of the organism.

Recent observations suggest that apoptosis, the natural, active cell death process is also triggered in several pathological conditions including ischemic brain insult, and neurodegenerative and autoimmune diseases. We have investigated the mechanisms involved in the development of apoptosis in neuronal and pancreatic cells and in macrophages, which were exposed to either chemical donors of nitric oxide or to inducers of the nitric oxide synthase. In this overview, we summarize current evidence for the involvement of apoptosis in the cytotoxicity of nitric oxide and discuss possible mechanisms that may lead to cell death.

The current state of knowledge investigating Tat interactions with signal transduction pathways is still in its infancy but has made significant progress toward understanding HIV pathology. This area is of great interest because Tat is among a small group of newly discovered RNA-based regulators of transcription. What is more important, however, are the implications of understanding these interactions concerning HIV-infected individuals. With the failure to develop effective HIV vaccines after years of development, it is becoming more feasible to conjecture therapies that target Tat as a means to keep HIV in its quiescent state rather than to eliminate the virus. In either case, the intense study of Tat and signal transduction pathways promises to provide a wealth of information about transcriptional control as well as the regulation of immune cell activation.

As neuroimmunologists, we are often faced with the fact that some substances can either enhance or inhibit particular immune/inflammatory cell functions. This ‘duality’ could only partially be explained by a dose-dependency and the fact that in a variety of systems, heterogenous cell populations are commonly used. For example it has been repetitively shown that cell proliferation, immunoglobulin synthesis and NK (natural killer) activity could be enhanced, inhibited or not affected at all by such neuropeptides as somatostatin (SOM) or vasoactive intestinal peptide (VIP), depending on the experimental conditions. Even substance P (SP), which, in general, stimulates lymphocyte activity, can, under certain conditions, possess an inhibitory activity. These apparent discrepancies between various groups and experimental conditions met with a strong reservation among ‘classical’ immunologists as they questioned the true physiological role that neuro-immune interactions play in normal and disease states. However, upon a detailed analysis of the data, it become obvious why such discrepancies abounded. Not only are we comparing totally different responses in different species, but almost always we compare different experimental conditions. In lieu of this, the reproducibility of the experiments within the same laboratory is in fact very high.

One fundamental and striking observation is the fact that at the level of a homogeneous cell population, a differential response could be evoked by the same neuropeptide over a range of concentrations.

For the purpose of this brief report we will focus on the cellular responses to the neuropeptide substance P and we will try to illustrate why such differential responses are possible. Some of the physiological data relating to the effects of SP on cell function will be discussed. This will be followed by a synopsis of SP receptor mechanisms on effector cells and finally the mechanism by which SP activates secondary messenger systems in these cells.

Using the recent burgeoning of information on how the stress response systems interact, and combining this with advances in our understanding of neuroimmune communication, a proposed neuroendocrine-neuroimmune stress response system incorporating autoimmunoregulation is reviewed. The study of immunocyte behavior in certain clinical conditions associated with a variant stress response may help illuminate the functioning of the neuroendocrine-neuroimmune stress response system.

We have demonstrated that human brain capillary endothelial (HBCE) cells, unlike umbilical or aortic endothelial cells are permissively infected by HIV. HIV infection of HBCE cells is noncytolytic and is mediated by a CD4- and GalCer-independent mechanism, implying that HBCE cell tropic strains utilize a unique receptor. The V3 loop of gp120 appears to be important in this reaction. T-cell tropic but not brain-derived macrophage tropic HIV strains selectively infect brain endothelium suggesting that T-cell tropism is important for HIV entry through the blood-brain barrier (BBB). The ability of HIV to infect cells that compose the BBB implies that the virus may be directly involved in the BBB dysfunction observed in

AIDS patients. HIV infection of HBCE cells may allow the flow of cytokines or toxic metabolites from the circulating blood into the brain parenchyma either by disrupting tight junctions or by altering the ability of the cells to regulate transport of substances across the BBB by transcytosis. HIV infection may also result in endothelial cell-induced astrocytosis by release of cytotoxic substances or modulation of abluminal surface antigens which contact astrocytic foot processes. Finally, HIV infection of the brain endothelium could facilitate virus entry to the CNS either by infection of HBCE cells or via entry of HIV-infected leucocytes. The establishment of our in vitro HIV-HBCE cell system will allow us to explore the potential mechanisms which mediate AIDS dementia.