Neuroendocrine properties of macrophage migration inhibitory factor (MIF)

The cytokine macrophage migration inhibitory factor (MIF) is produced by neuroendocrine and immune tissues and possesses several features that allow it to be characterized as a neuroendocrine mediator. Its pro-inflammatory action and its pathogenic role in inflammatory diseases, such as septic shock, arthritis and other diseases, have clearly been demonstrated and may be based in part on neuroendocrine mechanisms. Macrophage migration inhibitory factor possesses glucocorticoid-antagonist properties within the immune system and participates in the regulation of several endocrine circuits. This review summarizes the current state of MIF research and focuses on MIF expression and function in nervous and endocrine tissues.     

On the mechanisms and putative pathways involving neuroimmune interactions

Bidirectional interdependence between the immune system and the CNS involves the intervention of common cofactors. Cytokines are endogenous to the brain, endocrine and immune systems. These shared ligands are used as a chemical language for communication. Such interaction suggests an immunoregulatory role for the brain, and a sensory function for the immune system. Interplay between the immune, nervous and endocrine systems is associated with effects of stress on immunity. Cytokines are thus capable of modulating responses in the CNS, while neuropeptides can exert their effects over cellular groups in the immune system. One way is controlled by the HPA axis, a coordinator of neuroimmune interactions that is essential to unravel in order to elucidate vital communications in a manner that this crosstalk remains a cornerstone in perpetuating a stance of homeostasis.     

Cutting edge: clonally restricted production of the neurotrophins brain-derived neurotrophic factor and neurotrophin-3 mRNA by human immune cells and Th1/Th2-polarized expression of their receptors.

Neurotrophins, such as neurotrophin-3 (NT-3) and brain-derived neurotrophic factor (BDNF), are potent regulators of neuronal functions. Here we show that human immune cells also produce NT-3 mRNA, secrete BDNF, and express their specific receptors trkB and trkC. The truncated trkB receptor, usually expressed in sensory neurons of the central nervous system, was also constitutively expressed in unstimulated Th cells. Full-length trkB was detectable in stimulated PBMC, B cell lines, and Th1, but not in Th2 and Th0 cell clones. Clonally restricted expression was also observed for trkC, until now not detected on blood cells. The Th1 cytokine IL-2 stimulated production of trkB mRNA but not of trkC, whereas the Th2 cytokine IL-4 enhanced NT-3 but not BDNF mRNA expression. Microbial Ags, which influence the Th1/Th2 balance, could therefore modulate the neurotrophic system and thereby affect neuronal synaptic activity of the central nervous system.     

The neurochemical basis of cognitive deficits induced by brain iron deficiency: involvement of dopamine-opiate system.

Iron is an essential element in maintaining normal structure and functions of the central nervous system. Dangerous effects of decreases in the bioavailability of iron in the brain are shown to affect brain biochemistry, neurotransmitters production and function, mainly in the dopamine-opiate systems well as cognitive functions (learning and memory) and a number of physiological variables such motor activity and thermoregulation. Recent research has shown the added complications and deficits that are introduced in the endocrine and the immune system activity. While iron deficiency is not perceived as a life threatening disorder, it is the most prevalent nutritional disorder in the world and a better understanding of the modes and sites of action, can help devise better treatment programs for those who suffer from it.     

The GDNF family: from neurotrophic factors to oncogenesis

The structure and in vivo functions of the glial cell-derived neurotrophic factor (GDNF) family ligands (GFLs) and their high-affinity receptors are considered. These proteins play an important role in the development of the nervous system, morphogenesis of the kidneys, and in regulation of spermatogenesis. Tyrosine kinase Ret is a receptor component common for all GFLs. Its role in multiple endocrine neoplasia type 2 (MEN2) is discussed.     

Neurotrophic effect of Semaphorin 4D in PC12 cells

Semaphorins provide crucial attractive and repulsive cues involved in axon guidance during neural development. Out of them, Semaphorin 4D (Sema4D) is enriched in the nervous and immune tissues, and acts as proliferative and survival factors of peripheral lymphocytes in the immune system, but is poorly understood in the nervous system. By using PC12 cells which are well known to differentiate into neural cells in response to nerve growth factor (NGF), we found that soluble forms of Sema4D had neurotrophic effects which were inhibited by neutralizing antibodies to Sema4D. Sema4D strikingly potentiated neurite outgrowth in the presence of 50 ng/ml NGF and increased sensitivity to NGF. Cells responded to very low concentrations of NGF in the presence of 1 nM Sema4D. Activation of following signal proteins, protein kinase C (PKC), L-type of voltage-dependent Ca(2+) channel, and phosphatidylinositol (PI) 3-kinase mediated neurotrophic neurite-outgrowth action of Sema4D. These findings suggest a new function of Sema4D as a neurotrophic signal in PC12 cells.     

免疫细胞内源性儿茶酚胺的免疫调节作用

机体内儿茶酚胺（catecholamines,CAs）包括去甲肾上腺素（norepinephrine,NE）、肾上腺素（epinephrine,E）和多巴胺（dopamine,DA）。CAs由神经元和内分泌细胞合成和分泌,其主要功能是调节心血管、呼吸和消化等内脏活动。近三十年来的研究说明,CAs也参与调控机体的免疫功能,但CAs的这种免疫调节作用一般视为神经和内分泌系统调节的介导作用。然而,近年来的研究发现,免疫细胞也能合成CAs,这是对传统观念的一种补充和提高。免疫细胞内存在经典的CAs代谢途径,既有合成CAs的酪氨酸羟化酶（tyrosine hydroxylase,TH）又有降解CAs的单胺氧化酶（monoamine oxidase,MAO）和儿茶酚氧位甲基移位酶（catechol-O-methyl transferase,COMT）。免疫细胞合成的内源性CAs可以调控细胞的增殖、分化、凋亡和细胞因子生成等多种免疫功能。CAs的这些作用可能主要通过自分泌或旁分泌途径作用于免疫细胞上相应受体和细胞内环磷酸腺苷（cyclicAMP,cAMP）实现。细胞内氧化应激机制可能也参与免疫细胞内源性CAs的免疫调节作用。此外,一些自身免疫性疾病如多发性硬化、风湿性关节炎可能也与免疫细胞内CAs的代谢异常有关。上述发现不仅为免疫系统有可能成为除神经和内分泌系统以外的第三个CA能系统提供了证据,而且为免疫系统内源性CAs的功能意义拓展了认识。     

Interlationship between psychology and cytokines

Leukocytes and other types of cells produce proteins or glycoproteins, termed cytokines, that serve as chemical communicators from one cell to another. Neuromediators are able to modulate functions of immune cells and other cells and the relationship between the central nervous system (CNS) and the endocrine system have been known for many years. Communication between nerves and immune and inflammatory cells plays a major role in the modulation of several dysfunctions including ion transport, mucosal permeability and cytokine production. Cytokines are involved in both injury and repair, and the conditions underlying these distinct outcomes are under intense investigation and debate. Evidence from medical studies implicates the immune system in a number of psychiatric disorders with known or suspected developmental origins, including schizophrenia, anxiety-depression, and cognitive dysfunction.     

The GDNF Family: From Neurotrophic Factors to Oncogenesis

The structure and in vivofunctions of the glial cell-derived neurotrophic factor (GDNF) family ligands (GFLs) and their high-affinity receptors are considered. These proteins play an important role in the development of the nervous system, morphogenesis of the kidneys, and regulation of spermatogenesis. Tyrosine kinase Ret is a common receptor component for all GFLs. Its role in multiple endocrine neoplasia type 2 (MEN2) is discussed.     

Neurotrophins as mediators of drug effects on mood, addiction, and neuroprotection

The induction of synthesis or release of endogenous neurotrophic factors in the brain by low-molecular-weight drugs could be a feasible alternative for the direct administration of neurotrophic factors for the treatment of central nervous system disorders. Recent data suggest that several drugs already in clinical use increase the synthesis, release, or signaling of neurotrophins. Antidepressant drugs increase the synthesis and signaling of brain-derived neurotrophic factor (BDNF), and BDNF signaling appears to be both sufficient and necessary for the antidepressant-induced behavioral effects. Furthermore, neurotrophins and other neurotrophic factors play a role in the acute and chronic responses produced by addictive drugs. Moreover, several neuroprotective drugs influence neurotrophin synthesis or signaling, although the significance of these effects is still unclear. These findings reveal a wider role for neurotrophic factors in drug action than has previously been expected, and they suggest that neurotrophin-induced trophic responses in neuronal connectivity and plasticity may be involved in the mechanism of action of several classes of CNS drugs. Improved assay systems are needed for the systematic screening of the effects of putative neuroprotective drugs on the synthesis, release, and signaling of neurotrophic factors, and for the evaluation of the functional role of these factors in the action of novel drug candidates.     

Effects of interferon-gamma on the central nervous system

Pleotropic cytokine IFN-gamma is synthesized not only by activated immunocompetent cells but also by elements of CNS (endothelial cells of brain, glial cells, neurons). Primary structure of neuronal and immune IFN-gamma are similar. The molecular identity of this cytokine receptors on neuronal and immune cells is found. These facts testify of interrelation of two physiological systems. The central effects of IFN-gamma are realized in modulation both immune and controle-regulation processes. One of important immunomodulation properties of IFN-gamma is its ability to induce expression of antigenes of MHC class II on neuronal cells, which is characteristic only for this cytokine. The participation of IFN-gamma in immune reactions of CNS also is carried out at the expense of amplification under its influence of superoxide production, NO and prostaglandine synthesis, expression in astrocytes and microglial cells of ICAM adgesive molecule. Control-regulation function of cytokine is realized at level of cell elements of brain, nerve/endocrine system. Auto/parakrine activity of neuronal IFN-gamma is directed on maintenance homeostasis in CNS. It participates in regulation of processes connected to the daily allowance biorhythmes, it is revealed in work of "internal clocks". The cytokine participation in immunogenesis processes [symbol: see text] and control-regulation reactions has a number of common mechanisms. IFN-gamma is immunomodulator and from an other hand it is neuromodulator.     

Hypothalamic releasing hormones mediating the effects of interleukin-1 on sleep

There is a substantial literature describing the interactions between the endocrine and immune systems. Although such interactions are less well known within the brain, one major brain function altered during inflammation and infection and by several endocrine hormones is sleep. Pathological disturbances, be they inflammation, infectious disease, and/or sleep deprivation, result in altered hypothalamus-pituitary function and cytokine metabolism. In respect to hormone secretion from the pituitary, cytokines are now recognized to play an important role in modulating the neuroendocrine system. Changes in sleep provide a useful illustration of the interactions between cytokines and the hypothalamus-pituitary axis. Evidence linking interleukin-1 (IL-1) to growth hormone releasing hormone and to corticotropin releasing hormone in regard to their effects on sleep is reviewed.     

Leptin action on nonneuronal cells in the CNS: potential clinical applications

Leptin, an adipocyte-derived cytokine, crosses the blood-brain barrier to act on many regions of the central nervous system (CNS). It participates in the regulation of energy balance, inflammatory processes, immune regulation, synaptic formation, memory condensation, and neurotrophic activities. This review focuses on the newly identified actions of leptin on astrocytes. We first summarize the distribution of leptin receptors in the brain, with a focus on the hypothalamus, where the leptin receptor is known to mediate essential feeding suppression activities, and on the hippocampus, where leptin facilitates memory, reduces neurodegeneration, and plays a dual role in seizures. We will then discuss regulation of the nonneuronal leptin system in obesity. Its relationship with neuronal leptin signaling is illustrated by in vitro assays in primary astrocyte culture and by in vivo studies on mice after pretreatment with a glial metabolic inhibitor or after cell-specific deletion of intracellular signaling leptin receptors. Overall, the glial leptin system shows robust regulation and plays an essential role in obesity. Strategies to manipulate this nonneuronal leptin signaling may have major clinical impact.     

VGF 及其衍生肽

神经肽VGF广泛存在于中枢神经系统和外周神经系统中,在垂体、肾上腺髓质、胃肠内分泌细胞和胰岛β细胞中亦有表达。神经细胞/内分泌细胞表达VGF多肽受到神经营养因子、神经元活性等因素的调控。目前证实,VGF及其衍生肽参与生物体的能量平衡、新陈代谢以及生殖发育等的凋节。在神经系统变性病及情感性精神障碍的相关研究也日益受到关注。本文就神经肽VGF及其衍生肽的生化、生理特性及病理生理作用做一综述。     

肝细胞生长因子在神经系统的研究进展

肝细胞生长因子是一多效性细胞因子。在神经系统发育和再生过程中,肝细胞生长因子作为神经营养因子发挥作用。本文就肝细胞生长因子的分子生物学特性以及在神经系统中的分布和生物学作用进行综述。     

VGF及其衍生肽

神经肽VGF广泛存在于中枢神经系统和外周神经系统中,在垂体、肾上腺髓质、胃肠内分泌细胞和胰岛B细胞中亦有表达。神经细胞／内分泌细胞表达VGF多肽受到神经营养因子、神经元活性等因素的调控。目前证实,VGF及其衍生肽参与生物体的能量平衡、新陈代谢以及生殖发育等的凋节。在神经系统变性病及情感性精神障碍的相关研究也日益受到关注。本文就神经肽VGF及其衍生肽的生化、生理特性及病理生理作用做一综述。     

Bisphenol A (BPA) and cell signaling pathways

Bisphenol A (BPA; 4,4′-isopropylidenediphenol) is an endocrine disruptor that is used as a material for the production of phenol resins, polyacrylates, polyesters, epoxy resins, and polycarbonate plastics. Endocrine-disruptive or toxic effects of BPA on living organisms through a number of cell signaling pathways have been reported. BPA induces carcinogenesis, reproductive toxicity, abnormal inflammatory or immune response, and developmental disorders of brain or nervous system through various cell signaling pathways. This review considers the literature concerning BPA and its association with cancer-related cell signaling pathways, reproductive toxicity-related cell signaling pathways, inflammatory or immune response-related cell signaling pathways, and brain and nervous system-related cell signaling pathways.     

Neuroimmunology: is the immune system a sense organ?

Through antigenic recognition, the immune system (SI) perceives an external information which is not directly perceptible by the central nervous system (SNC). So, two roles can be assigned SI: immuno-surveillance and information. Since 1980, it was proved that activated lymphocytes and others elements involved in the expression of immune response are able to secrete hormones, neuromediators and peculiar secretions. Moreover, the immune elements possess receptors for SNC secretions. A direct relations between lymphocytes, hypothalamus, hypophysis and endocrine glands has been suggested with implications in the understanding of some mental diseases and conditioning of the immune response. This view of immunoregulation confers a role of mobile brain or sensory organ to the SI.