ISSN:0736-5748    

DOI:10.1016/0736-5748(95)90000-4

出版商:Wiley    

年代:2004

数据来源: WILEY

摘要:

AbstractThe action of immune‐system‐derived cytokines to stimulate the release of corticotropin‐releasing factor (CRF) from the hypothalamus and the consequent elaboration of ACTH and release of corticosteroids has provided an especially useful model to investigate the nature of the intercommunication of neuroendocrine and immunological pathways. Substantial evidence exists to support the production of cytokines, such as interleukin‐1 (IL‐1) α and β, within the mammalian central nervous system. The mechanisms and neuronal circuitries involved in the effects of these cytokines of peripheral and central origin on the activity of neuroendocrine CRF motoneurons and the hypothalamic‐pituitary‐adrenal axis are described. Also included is a discussion of the influence of IL‐1 on transduction signals controlling the release and the biosynthesis of CRF in the parvocellular division of the paraventricular nucleus of the hypothalamus and the relationship between these two distinct intracellular processes. The relebance of using immediate early genes as indices of neuronal activity in immune‐challenged rats and the possible roles of c‐fosand NGFI‐B within neuroendocrine CRF motoneurons are outlined. Finally, the effects of acute immune response on neuroendocrine functions and brain neuronal activation are presented.

ISSN:0736-5748    

DOI:10.1016/0736-5748(94)00063-9

出版商:Wiley    

年代:1999

数据来源: WILEY

摘要:

AbstractNeurotrophins (NTs), including nerve growth factor (NGF), are multifunctional: in addition to their well‐characterized neurotrophic functions they are known to regulate and to be regulated by cytokines, components of the immune system. In line with this we have found expression of a functional trk proto‐oncogene, constituting the signal transducing‐receptor for NGF, on monocytes/macrophages, lymphocytes and basophils. Moreover, NGF synthesis is regulated by a cytokine cascade including inflammatory mediators such as interleukin‐1 and tumor necrosis factor‐α. The fact that NGF levels are markedly elevated in cerebrospinal fluid of patiens with multiple sclerosis and in serum of patients with systemic lupus erythematosus strongly indicates a role for NGF in immunopathology as well as in normal immune function.

ISSN:0736-5748    

DOI:10.1016/0736-5748(95)00016-A

出版商:Wiley    

年代:1999

数据来源: WILEY

摘要:

AbstractIn this paper, we discuss the potential involvement of a new family of cytokines, termed chemokines, in CNS inflammatory pathology. Chemokines are a family of proinflammatory cytokines which are able to stimulate target‐cell‐specific directional migration of leukocytes. Because of this feature, chemokines may be potent mediators of inflammatory processes. We have previously reported observations indicating that chemokines may be involved in the process of lesion formation during autoimmune inflammation within CNS, and, in particular, are likely participants in the process of influx of inflammatory cells into the CNS parenchyma. We observed also that mechanical injury of brain and subsequent post‐traumatic inflammation may in part be mediated by chemokines. Chemokines undoubtedly co‐operate with cell‐associated adhesion molecules during recruitment of leukocytes from blood to CNS. The sequential expression of soluble and membrane‐bound signals for leukocyte migration is an intricate process that can be interrupted by a variety of strategies. Our data suggest that chemokines may represent a promising target for future therapy of inflammatory conditions, including CNS inflammation resulting from varied insults.

ISSN:0736-5748    

DOI:10.1016/0736-5748(95)00017-B

出版商:Wiley    

年代:1999

数据来源: WILEY

摘要:

AbstractInterleukin‐1 (IL‐1) receptors with kinetics, pharmacological and biochemical characteristics of type I IL‐1 receptors have been identified in the mouse neuro‐endocrine‐immune axis. In the present study, we examined thein‐vitroandin‐vivomodulation of IL‐1 receptors by stress and endotoxin treatment. The treatment of AtT‐20 mouse pituitary adenoma cells for 24 hr with neuro‐endocrine mediators of stress such as corticotropin releasing factor (CRF) and catecholamine (β2adrenergic) receptor agonists produced a dose‐dependent increase in cAMP and [125I]IL‐1α binding. In contrast, somatostatin and dexamethasone significantly inhibited CRF‐stimulated cAMP production and decreased both basal and CRF‐mediated increase of [125I]IL‐1α binding. Furthermore, in keeping with the effects of stress mediators to upregulate IL‐1 receptors in AtT‐20 cells, ether‐laparotomy stress in mice resulted in a significant increase in [125I]IL‐1α binding in the pituitary with no significant alterations observed in the brain; in contrast, [125I]oCRF binding in the pituitary was significantly decreased after the ether‐laparotomy stress.Next, we investigated the modulation of IL‐1β levels and [125I]IL‐1α binding following endotoxin lipopolysaccharide (LPS) treatment. IL‐1β levels were dramatically increased in the peripheral tissues (pituitary, tests and spleen) at 2–6 hr after a single LPS injection (30 μg LPS/mouse) However, no significant changes were observed in brain (hippocampus and hypothalamus). [125I]IL‐1α binding in the pituitary gland, liver, spleen and testis was significantly decreased at 2 hr following a single administration of both low (30 μg LPS/mouse) and high (300 μg LPS/mouse) doses of endotoxin. [125I]IL‐1α binding in the hippocampus was not significantly altered at 2 hr by a low dose of LPS and was significantly decreased by high dose administration of LPS (300 μg/mouse). Following two LPS injections (at 0 and 12 hr), dramatic increases in IL‐1β concentrations in the hypothalamus, hippocampus, spleen and testis were observed at 2 hr after the second LPS injection; a small but statistically nonsignificant change was evident in the pituitary. Moreover, dramatic decreases in [125I]IL‐1α binding were seen after two injections of 30 μg LPS/mouse in both central and peripheral tissues. These data provide further support for a role for IL‐1 in co‐ordinating neuro‐endocrine‐immune responses to stress and infection.

ISSN:0736-5748    

DOI:10.1016/0736-5748(95)00015-9

出版商:Wiley    

年代:1999

数据来源: WILEY

摘要:

AbstractCytokines have diverse actions in the brain, some of which may facilitate either neurodegeneration or neuroprotection. The expression of cytokines, particularly interleukins‐1 and ‐6 (IL‐1, IL‐6) and tumor necrosis factor α, is rapidly and markedly induced in response to experimentally induced or clinical neurodegeneration. We have demonstrated that central administration of the IL‐1 receptor antagonist (IL‐1ra) markedly inhibits neurodegeneration induced by focal cerebral ischaemia, local infusion of glutamate receptor agonists or traumatic brain injury in the rat. In contrast, IL‐1ra offers no protection against degeneration of primary cortical neurones in culture caused by exposure to agonists of ionotrophic or metabotrophic receptors.In vivo, administration of IL‐1β exacerbates ischaemic brain damage, whereas in cell culture, exogenous IL‐1 is neuroprotective at concentrations in the nM range, an effect which appears to be mediated by release of endogenous nerve growth factor. Higher concentrations of IL‐1 (μM range) are neurotoxic to neurones in culture and may mimic the involvement of IL‐1 in neurodegenerationin vivo. Thus, excessive production of cytokines such as IL‐1 appears to mediate experimentally induced neurodegenerationin vivo, while neuroprotective effects of low concentrations of the cytokine suggest a dual role for IL‐1 in neuronal survival.

ISSN:0736-5748    

DOI:10.1016/0736-5748(95)00018-C

出版商:Wiley    

年代:1999

数据来源: WILEY

摘要:

AbstractA neurotrophic role for interleukin‐1 alpha (IL‐1α) was investigated in dissociated spinal cord‐dorsal root ganglion cultures. Three observations suggested a survival‐promoting action for IL‐1α in nine‐day‐old cultures: (1) neutralizing antiserum to murine IL‐1α decreased neuronal survival; (2) treatment with IL‐1α in electrically blocked cultures increased neuronal survival; and (3) antiserum to the type I IL‐1 receptor decreased neuronal survival. Treatment with VIP prevented neuronal cell death associated with the antiserum to IL‐1α. In contrast, treatment of one‐month‐old cultures with IL‐1α produced neuronal cell death and neutralizing antiserum to the IL‐1 receptor had no effect on neuronal survival in these cultures. These experiments suggested that an IL‐1‐like substance was necessary for neuronal survival during a specific stage in development and that a relationship between VIP and IL‐1α might account in part for the neurotrophic properties of VIP.To test if VIP might be a secretagogue for IL‐1, a neuron‐free model system was utilized: astroglial cultures derived from cerebral cortex. VIP treatment produced a concentration‐dependent (EC50:50 pM) increase in the amount of IL‐1α in the medium and a decrease in cellular IL‐1α. Interleukin‐1 beta (IL‐1β) was also increased (EC 50: 1 nM) in the medium by VIP but without depleting IL‐1β in the cytosol. Semi‐quantitative measurements of the IL‐1α mRNA after VIP treatment indicated a significant but transient decrease. These data indicate that VIP produced an increase in the secretion of IL‐1α while depleting IL‐1α mRNA.

ISSN:0736-5748    

DOI:10.1016/0736-5748(95)00014-8

出版商:Wiley    

年代:1999

数据来源: WILEY

摘要:

AbstractThe present study was undertaken to assess the effects of interleukin‐1β (IL‐1β) and interleukin‐2 (IL‐2) on glial and neuronal cells in culture. The presence of IL‐1β‐like and IL‐2‐like immunoreactivity was detected in media collected from both astroglial and microglial cultures, indicating that both lymphokines can be released from either cell type. However, the levels measured in microglial media were significantly higher than in the astroglial media. Moreover, the content of IL‐1β‐like immunoreactive material in the media was approximately five‐ to 10‐fold greater than that of IL‐2, although exposure of both microglial and astroglial cultures to IL‐1β significantly enhanced this measure. A possible role for this glial‐derived IL‐1β as an astroglial growth factor was substantiated by experiments showing that the lymphokine increased the incorporation of [3H]thymidine into astroglial, but not microglial cultures. In contrast, IL‐2 did not significantly alter glial proliferation. In hippocampal neuronal cultures, these lymphokines affected neuronal survival differently. Thus, only the highest concentration (500 ng/ml) of IL‐1β tested decreased the long‐term (three day), but not the short‐term (one day), survival of these neurons, whereas neuronal survival was compromised by IL‐2 even after short‐term (one day) exposure. In addition, in the long‐term (three‐day‐old) neuronal cultures exposed to IL‐2, extensive cellular swelling, vacuolations and neurite retractions were noted, even in cultures exposed to relatively low concentrations (<10 ng/ml) of the lymphokine. These effects were not apparent with IL‐1β or the other lymphokines tested, including IL‐3, IL‐4 and IL‐8. The results suggests that the glial‐derived lymphokines IL‐1β and IL‐2 may have different functions in the CNS. Whereas IL‐1β may have an important role in the developing brain as a maintenance and growth‐promoting factor, IL‐2 may function as an inhibitory factor, and may be of significance only in instances during which it accumulates in sufficiently high concentrations in the vicinity of neurons.

ISSN:0736-5748    

DOI:10.1016/0736-5748(94)00072-B

出版商:Wiley    

年代:1999

数据来源: WILEY

摘要:

AbstractThe patterns and mechanisms of action of inductive signals that orchestrate neural lineage commitment and differentiation in the mammalian brain are incompletely understood. To examine these developmental issues, we have utilized several culture systems including conditionally immortalized cell lines, subventricular zone progenitor cells and primary neuronal cultures. A neural stem and progenitor cell line (MK31) was established from murine embryonic hippocampus by retroviral transduction of temperature‐sensitive alleles of the simian virus 40 large tumor antigen. At the non‐permissive temperature for antigen expression (39°C) in serum‐free media, the neural stem cells give rise to a series of increasingly mature neuronal progenitor and differentiated cellular forms under the influence of a subset of hematolymphopoietic cytokines (interleukins 5, 7, 9 and 11), when individually co‐applied with transforming growth factor α, after pretreatment with basic fibroblast growth factor. These cellular forms elaborated a series of progressively more mature neurofilament proteins, a sequential pattern of ligand‐gated channels, and inward currents and generation of action potentials with mature physiological properties. Because the factors regulating the development of central nervous system astrocytes have been so difficult to define, we have chosen to focus, in this manuscript, on the elaboration of this cell type. At 39°C, application of a subfamily of bone morphogenetic proteins of the transforming growth factor β superfamily of growth factors sanctioned the selective expression of astrocytic progenitor cells and mature astrocytes, as defined by sequential elaboration of the Yb subunit of glutathione‐S‐transferase and glial fibrillary acidic protein. These lineage‐specific cytokine inductive relationships were verified using subventricular zone neural progenitor cells generated by the application of epidermal growth factor, alone or in combination with basic fibroblast growth factor, to dissociated cellular cultures derived from early embryonic murine brain, a normal non‐transformed developmental population. Finally, application of a different series of cytokines from five distinct factor classes (basic fibroblast growth factor, platelet‐derived growth factor‐AA, insulin‐like growth factor 1, neurotrophin 3 and representative gp130 receptor subunit‐related ligands) caused the elaboration of oligodendroglial progenitor species and post‐mitotic oligodendrocytes, defined by progressive morphological maturation and the expression of increasingly adbanced oligodendroglial and oligodendrocyte lineage markers. In addition, seven different gp130‐associated neuropoietic (ciliary neurotrophic factor, leukemia inhibitory factor, oncostatin‐M) and hematopoietic (interleukins 6, 11, 12, granulocyte‐colony stimulating factor) cytokines exhibited differential trophic effects on oligodendroglial lineage maturation and factor class interactions. Examination of the expression of hematolymphopoietic cytokines and their receptors in brain and neural cultures has confirmed that these epigenetic signals are present at the appropriate development times to mediate their neurotrophic actions. These cytokines signal through alternate receptor subunit motifs distinct from those of the traditional neurotrophins. The bone morphogenetic protein ligand, in particular, exhibit a complex spatiotemporal pattern of transcript expression that suggests a broad spectrum of developmental roles for these transforming growth factor β subclass factors.To examine the cellular action of the bone morphogenetic proteins on astroglial lineage elaboration in greater detail, we utilized several complementary developmental systems. When primary neuronal cultures from multiple brain regions of mid‐gestational (embryonic day 15) fetuses in serum‐free media were exposed to the same combination of bone morphogenetic proteins that sanctioned astroglial lineage elaboration from neural stem and progenitor cells, they exhibited significant suppression of neuronal viability. By contrast, application of the same factors to late embryonic day 17–18 neuronal cultures resulted in a regional and factor‐specific potentiation of cellular survival and differentiation. The neurotrophic effects of the bone morphogenetic proteins appear to be indirect and mediated by stimulation of non‐neuronal cells. Further, application of the bone morphogenetic proteins to purified O‐2A progenitor cells, derived from early postnatal brain and from a clonal progenitor cell line resulted in the selective induction of type II astrocytes, suggesting that these transforming growth factor β subclass factors are acting directly on these bipotent astrocytic/oligodendroglial progenitor cells. These diverse experimental observations suggest that a single central nervous system neural stem cell can give rise to all three major cellular elements of the mammalian brain. Cytokines from the three major growth factor superfamilies (neurotrophins, hemopoietins and transforming growth factor β‐related factors) exhibit a differential pattern of neurotrophic actions on distinct central nervous system lineage species during sequential developmental stages. These observations suggest that a complex hierarchy of interacting epigenetic signals is required for central nervous system neurogenesis.

ISSN:0736-5748    

DOI:10.1016/0736-5748(94)00060-G

出版商:Wiley    

年代:1999

数据来源: WILEY

摘要:

AbstractWe examined the effects of interleukin‐3 (IL‐3) and other hematopoietic cytokines on the neurotransmitters, neurite formation, and differentiation in cholinergic and other types of neurons. IL‐3, granulocyte‐macrophage colony‐stimulating factor (GM‐CSF), macrophage colony‐stimulating factor, granulocyte colony‐stimulating factor and erythropoietin (Epo) elevated choline acetyltransferase (ChAT) activity in septal cholinergic cell line SN6 as well as in primary cultured septal neurons without increasing protein contents of the cells. These effects were dose‐dependent and the optimal doses were not different from those for blood cells. IL‐3 had neurite‐promoting activity but GM‐CSF had no such effect. Both IL‐3 and GM‐CSF decreased intracellular acetylcholine concentration, and elevated glutamic acid decarboxylase and intracellular GABA in septal neuronal cultures. Epo elevated monoamines in PC12 cells. These effects are thought to result from direct action through their specific receptors in neurons, because (i) anti‐IL‐3‐receptor antibody abolished the ChAT activity in septal neurons increased by IL‐3; (ii) mRNA and immunoreactivity for β subunits of IL‐3 receptors were expressed in septal cholinergic neurons and (iii) presence of receptos for GM‐CSF and Epo in neurons has been reported. Our observation and others strongly support that neural‐immune interactions are important not only in the defense mechanism in the nervous system but also in the development, differentiation and function of neurons.

ISSN:0736-5748    

DOI:10.1016/0736-5748(94)00020-4

出版商:Wiley    

年代:1999

数据来源: WILEY