摘要:

AbstractCells resident within the central nervous system (CNS) can synthesize, secrete and respond to inflammatory cytokines not only contributing to the responses to injury or immunological challenge within the CNS, but also regulating their own growth and differentiation potential. The actions and cell communication via cytokines in the CNS are designated as the CNS cytokine network, in which microglia and astrocytes play the central roles. To further characterize the CNS cytokine network we investigated the differences in roles of these cells, and found that microglia might contribute to the early phase of cytokine production reaction and that astrocytes might contribute the late phase of the reaction. We also investigated roles of inhibitory cytokines such as TGF β, IL‐4, and IL‐10, and showed that each might play a distinct role in the inhibitory regulation in the CNS. We summarized our previous report about cellular distribution of cytokine receptors in the CNS cells and discussed their roles in the CNS cytokine network. Finally, we investigated that expression of IL‐6 and IL‐2 receptors in neuronal and oligodendrocytic differentiation, respectively. From these results, we discussed the features of the CNS cytokine network.

ISSN:0736-5748    

DOI:10.1016/0736-5748(94)00076-F

出版商:Wiley    

年代:1999

数据来源: WILEY

摘要:

AbstractParticipation of astrocytes in central nervous system pathophysiology is likely to involve cytokines, both as stimulators and mediators of astrocyte function. We have used highly enriched human astrocyte cultures as an experimental tool to investigate the influence of cytokines on adhesion molecule expression and synthesis of mediators that are probably important in immune and inflammatory reactions involving the nervous system and in cerebral tissue repair. The response of astrocytes to interferon‐γ mainly resulted in increased expression of major histocompatibility complex antigens and co‐stimulatory molecules (intercellular adhesion molecule‐1, LFA‐1α) which mediate astrocyte‐T‐cell interactions. Another co‐stimulatory molecule, B7, was neither expressed nor inducible by IFN‐γ and other cytokines. TNF‐α and IL‐1β were more efficient in stimulating synthesis of immunoregulatory and proinflammatory cytokines (IL‐6, IL‐8 and colony‐stimulating factors), cytokine antagonists (TNF‐α soluble receptors), or cytokines with a possible neuroprotective role (leukemia inhibitory factor); they also increased expression of some co‐stimulatory molecules (intercellular adhesion molecule‐1 and vascular cell adhesion molecule‐1). Transforming growth factor‐β1was a strong inducer of leukemia inhibitory factor, but did not affect either major histocompatibility complex/co‐stimulatory molecule expression or cytokine synthesis. Thus, different cytokines activate distinct functional programs in astrocytes, which may play a specific role in different brain diseases or at different stages of the same disease. It was additionally observed that the response of human astrocytes to cytokines (in particular the inducible synthesis of certain cytokines) varied greatly depending on the presence or absence of neurons in the culture system. This finding suggests that neuronal‐glial interactions may be implicated in determining the activation threshold of astrocytes to inflammatory cytokines.

ISSN:0736-5748    

DOI:10.1016/0736-5748(94)00071-A

出版商:Wiley    

年代:1999

数据来源: WILEY

摘要:

AbstractCytokines are potent biological response modifiers that exhibit a spectrum of cellular actions. These factors have been implicated as important mediators of physiologic and possibly pathophysiologic processes within the CNS. Targeting the expression of cytokines to specific tissues in transgenic mice has provided a powerful approach to the investigation of complex cellular responses at a localized level and also recapitulated more closely the expression of these mediators as found in pathogenetic processes. This review will focus on the recent application of transgenic technology to achieve the specific cerebral expression of cytokines. The targeting of cytokine gene expression to astrocytes in transgenic mice has provided new and dramatic insights into the CNS pathobiology of these host‐response molecules. Specifically: (1) transgenic expression of the cytokines IL‐6, IL‐3 and IFN‐α in the CNS results in the development of acute (high expression) or chronic progressive (low expression) CNS disease associated with a spectrum of clinical, physiologic and pathologic manifestations; (2) although the clinical, cellular and molecular phenotype produced by the cerebral expression of the various cytokines showed some overlap, the differences were more prominent reflecting the unique actions of each cytokine; (3) these transgenic models which recapitulate many of the structural and functional impairments seen in human neurodegenerative diseases, highlight the point that cytokines, which normally function as primary regulators of the host response, also have the potential to mediate significant injury in the CNS. Therefore, these transgenic models have provided a valuable tool for adbancing our understanding of the CNS pathobiology of cytokines and will no doubt offer a unique resource for the development and testing of therapies aimed at abrogating the toxic actions of these important mediators.

ISSN:0736-5748    

DOI:10.1016/0736-5748(94)00073-C

出版商:Wiley    

年代:1999

数据来源: WILEY

摘要:

AbstractIn this study we usedop/opmice, which are deficient in the hematopoietic cytokine, colony‐stimulating factor 1 (CSF‐1), to determine the effect of CSF‐1 on neuronal survival and microglial response in injury. In normal mice microglia express the CSF‐1 receptor and are primarily regulated by CSF‐1, produced mainly by astrocytes. The CSF‐1 deficiency inop/opmice results in a depletion in the number of monocytes and macrophages but does not affect the number of morphology of microglia. We produced an ischemic lesion in the cerebral cortex of mice by disrupting the pia‐arachnoid blood vessels in a defined area. Using Nissl stain and strocyte‐ and microglia‐specific antibodies, we determined the number of viable neurons in such injury and the intensity of glial reaction. The cellular response to injury on the operated side ofop/opmice was compared to that on the non‐operated contralateral side and to the cellular response in similar lesions in CSF‐1 producing C3H/HeJ mice. We found that the systemic lack of CSF‐1 inop/opmice results in a significant increase in neuron vulnerability to ischemic injury and considerably reduced microglial response to neuron injury. Remedying the CSF‐1 deficiency, either by grafting CSF‐1 secreting astroglia into the brain or by implanting encapsulated CSF‐1 secreting fibroblast‐like cells into the peritoneum, partially restores the microglial response to neuron injury and significantly potentiates neuronal survival in cerebral cortex ischemic lesions. Astroglial reaction was approximately the same in the lesions inop/opmice, grafted annd implantedop/opmice and C3H/HeJ mice, indicating that CSF‐1 modulates microglia, but not the response of astrocytes to injury. The degree of neuronal survival was not correlated to the degree of microglial proliferation and intensity of their reaction. We report some indications that CSF‐1, in addition to modulation of microglia, may also act directly on neurons.

ISSN:0736-5748    

DOI:10.1016/0736-5748(95)00013-7

出版商:Wiley    

年代:1999

数据来源: WILEY

ISSN:0736-5748    

DOI:10.1016/0736-5748(94)00062-8

出版商:Wiley    

年代:1999

数据来源: WILEY

摘要:

AbstractA number of cytokine families have been implicated in shaping neuronal survival, growth and gene expression. The neuropoietic and transforming growth factor‐β (TGF‐β) cytokines, in particular, have emerged as candidates for regulating the phenotype of sympathetic neurons. Culture studies have shown that neuropoietic cytokines (such as leukemia inhibitory factor, ciliary neurotrophic factor, oncostatin M, growth promoting activity) can induce the cholinergic enzyme, choline acetyltransferase (ChAT) and several neuropeptides, whereas certain members of the TGF‐β family (activin A, bone morphogenetic proteins‐2 and ‐6) induce partially overlapping but distinct sets of transmitter and neuropeptide genes in sympathetic neurons.Since activins can induce ChAT in cultured neurons, we have investigated whether these cytokines are expressed by the appropriate cells and tissues to make them candidates for the cholinergic differentiation factor that is known to alter the phenotype of sympathetic neurons that innervate the sweat gland in the footpadin vivo. In‐situhybridization with the anti‐sense probe for activinβBspecifically labels the sweat glands but not other tissues in the footpads of developing rats. Ribonuclease protection assays indicate thatβBas well as the other activin and inhibin subunit mRNAs are expressed by a number of tissues, including footpad, hairy skin and submaxillary gland. Homogenates of developing rat footpads, however, failed to induce the set of neuropeptide genes in cultured sympathetic neurons that is characteristic for activins, although neuropoietic cytokine activity was readily detectable in this assay. Thus, while activinβBmRNA is expressed in the sweat gland, this tissue does not contain detectable activin protein as assayed by its ability to regulate neuronal gene expression. Moreover, activin subunit mRNAs are expressed by targets of noradrenergic sympathetic neuronsin vivo, indicating that activin expression is not limited to targets of cholinergic neurons.

ISSN:0736-5748    

DOI:10.1016/0736-5748(94)00075-E

出版商:Wiley    

年代:1999

数据来源: WILEY

摘要:

AbstractLesions to the nervous system are nearly universally accompanied by a glial response involving both microglia and astrocytes. The growth and immunoregulatory cytokine transforming growth factor‐β1 (TGF‐β1) has potent effects on glial cellsin vitroand may play a role in regulating glial activationin vivo. Though present only at very low levels in the normal brain, TGF‐β1 mRNA is strongly upregulated in a number of different experimental models suitable to study glial responses. Following axotomy of the facial nerve of the rat, about a three‐fold increase of TGF‐β1 mRNA in the regenerating nucleus was observed with a time‐course closely matching that of glial activation. Putative activated microglial cells are the major cellular source as revealed byin‐situhybridization. TGF‐β1 was also found to be upregulated around brain tumors, in the spinal cord in response to peripheral nerve inflammation and in the postishemic hippocampus. In all systems investigated, TGF‐β1 mRNA could be localized predominantly to cells with the typical nuclear morphology of microglia. In the peripheral nervous system, nerve transection leads to a massive increase in TGF‐β mRNA expression both proximal and distal to the cut site. However, whereas TGF‐β1 mRNA is restricted to the nerve stump in the proximal segment, expression is diffuse and widespread throughout the denervated distal segment where it was localized mainly to cells with macrophage morphology. Thus, TGF‐β appears to be uniformly expressed by microglial cells of the central nervous system whenever these cells become activated and might be required for microglial cells to control their own activation and cytotoxicity. In addition, our data suggest that TGF‐β1 might also be regulating cellular responses in the peripheral nervous system in response to injury.

ISSN:0736-5748    

DOI:10.1016/0736-5748(94)00074-D

出版商:Wiley    

年代:1999

数据来源: WILEY

摘要:

AbstractIn this study, we demonstrate that transforming growth factor‐beta (TGF‐β), interleukin‐10 (IL‐10) and interleukin‐6 (IL‐6) inhibit tumor necrosis factor‐alpha expression by primary rat astrocytes. Treatment of astrocytes with TGF‐β alone had no effect on TNF‐α expression, however, TGF‐β suppressed induction on TNF‐α expression at both the protein and mRNA level. In contrast, IL‐10 and IL‐6 both inhibited TNF‐α protein expression by astrocytes, but had no effect on mRNA levels. The extent of IL‐6 mediated inhibition was greatest when astrocytes were pretreated with IL‐6 for 12–24 hr, then exposed to the inducing stimuli, while IL‐10 was an effective inhibitor even when added simultaneously with the inducing stimuli. Collectively, these data indicate that TGF‐β, IL‐6 and IL‐10 are all capable of inhibiting TNF‐α expression by astrocytes, although these immunosuppressive cytokines act at different levels of gene expression; i.e. TGF‐β at the transcriptional level and IL‐10/IL‐6 at the translational level. These results indicate that TGF‐β, IL‐6 and IL‐10 are important regulators of cytokine production by astrocytes under inflammatory conditions in the brain, and can contribute to controlling the production of detrimental cytokines such as TNF‐α.

ISSN:0736-5748    

DOI:10.1016/0736-5748(94)00061-7

出版商:Wiley    

年代:1999

数据来源: WILEY

摘要:

AbstractWe have used a combination of electrophysiological and biochemical approaches to investigate the effects and the mechanisms of action of tumor necrosis factor‐α (TNF‐α) on cultured oligodendrocytes (OLGs). Our studies have led to the following conclusions: (1) prolonged exposure of mature ovine OLGs to TNF‐α leads to inhibition of process extension, membrane depolarization and a decrease in the amplitudes of both inwardly rectifying and outward K+currents; (2) brief exposure of OLGs to TNF‐α does not elicit membrane depolarization or consistent changes in cytosolic Ca2+levels; (3) incubation of OLGs with TNF‐α for 1 hr results in inhibition of phosphorylation of myelin basic protein and 2′, 3′‐cyclic nucleotide phosphohydrolase. Ceramides, which have been shown to be effectors of TNF‐α, are ineffective in inhibiting phosphorylation, whereas sphingomyelinase mimicks TNF‐α in this action. These observations suggest that other products of sphingomyelin hydrolysis may be the mediator(s) of TNF‐α effect on protein phosphorylation. We have thus demonstrated that TNF‐α can perturb the functions of OLGs via modulation of ion channels and of protein phosphorylation without necessarily inducing cell death. It is conceivable that modulation of ion channels and protein phosphorylation constitutes effective mechanisms for the participation of cytokines in signal transduction during myelination, demyelination and remyelination.

ISSN:0736-5748    

DOI:10.1016/0736-5748(95)00019-D

出版商:Wiley    

年代:1999

数据来源: WILEY

摘要:

AbstractCytokines produced by infiltrating hematogenous cells or by glial cells activated during the course of central nervous system disease or trauma are implicated as mediators of tissue injury. In this study, we have assessed the extent and mechanism of injury of human‐derived CNS oligodendrocytes and neuronsin vitromediated by the cytokines tumor necrosis factor α and β and compared these with the tumor necrosis factor independent effects mediated by activated CD4+T‐cells. We found that activated CD4+T‐cells, but not tumor necrosis factor α or β, could induce significant release of lactate dehydrogenase, a measure of cell membrane lysis, from oligodendrocytes within 24 hr. Neither induced DNA fragmentation as measured using a fluorescence nick‐end labelling technique. After a more prolonged time period (96 hr), tumor necrosis factor α did induce nuclear fragmentation changes in a significant proportion of oligodendrocytes without increased lactate dehydrogenase release. The extent of DNA fragmentation was comparable to that induced by serum deprivation. Tumor necrosis factor β effects were even more pronounced. In contrast to oligodendrocytes, the extent of DNA fragmentation, assessed by propidium iodide staining, induced in neurons by tumor necrosis factor α was less than that induced by serum deprivation.In‐situhybridization studies of human adult glial cells in culture indicated that astrocytes, as well as microglia, can express tumor necrosis factor α mRNA.

ISSN:0736-5748    

DOI:10.1016/0736-5748(95)00012-6

出版商:Wiley    

年代:1999

数据来源: WILEY