425
Dossier
Cytokines
as mediators
in the central
“Cytokines”
nervous system
Summary - Cytokines are soluble mediators involved in cell-cell regulations in the immunological and the hematopoietic system. We review various cytokine effects on the central nervous system, including growth-promoting activity, neuromodulatory action. fever induction, sleep and decreased food intake. In addition, cytokines, neuropeptides, neurotransmitters and hormones all participate in an intricate inter-relationship to contribute to the development and maintenance of brain homeostasis. Cytokines are also involved in the wounding responses of injured brain after trauma, infection or neurodegenerative processes. Pharmacological modulation of the expression and/or actions of cytokines in the brain may represent a new field of research of therapeutic benefit in the treatment of central disorders. cytokines
/central
nervous
system
I neuropathologies
Introduction Cytokines are soluble mediators involved in the regulation of immunological processes, although they also exhibit other biological functions, eg on the neuroendocrine system. They are actively implicated in the communication between the brain and the immune system under normal physiological conditions as well as in brain pathologies when the blood-brain barrier (BBB) is altered. Moreover, it appears that the brain is no longer the immunologically deprived site it was thought to be. There is now growing evidence that the central nervous system (CNS) is able to develop immune reactions. The discovery of new cytokines remains an intensive.field of research. The most recently discovered is IL 13 [36], which extends the list of lymphokines regulating inflammatory and immune responses. Cytokines are characterized by complementary and counteractive pleiotropic, biological actions. They display a range of biological activities, generally by reacting with their own receptor. These membrane receptors transduce intracellular signals. However, another form of cytokine receptors has been described: soluble forms that occur naturally, have been identified for TNFa, IL6 and IL4. In addition, several endogenous cytokine inhibitors have been evidenced. They attenuate cytokine effects in various cell
types: they compete with the corresponding cytokines for binding to its receptor (eg ILl), or they bind the cytokines and block their ability to bind to their receptor (eg TNF). Only a few cytokines have been studied in the CNS, where they may represent a new signalling pathway. Studies on cytokines performed in nonCNS tissues show that they have effects on cells distant from the cells of origin, participating in circulating or adherent cell-cell communication. They thus differ from neurotransmitters and neurotrophic factors, which travel only short distances and act very closely across the synapse [6]. The first part of this review focuses on the cellular sources of cytokines in the CNS, and their effects. We then present an overview of the roles of cytokines in different CNS pathologies, including viral and bacterial infections, inflammation, traumatic injury and degenerative processes.
Cytokine synthesis, location and binding sites in the brain Cytokines found in the brain may be of peripheral origin, although the mechanism by which peripheral cytokines can penetrate into the brain is subjected to controversy. Cytokines enter the CNS at the circumventricular organ, across the BBB via saturable bidirectional transport, through the
426 BBB whose permeability is increased after trauma or inflammation when a leakage of the BBB appears [5]. Furthermore, they may be synthesized by the entering activated T lymphocytes. Cytokines are produced by a variety of cells including resident cells within the CNS, particularly astrocytes and microglia. The existence of brain cytokines was first investigated by in vitro studies. Cytokines messenger RNAs were identified by northern blot analysis and polymerase chain reaction in glioblastoma cell lines and in primary cultured cells such as astrocytes and microglia [ 191. Recent data demonstrate that neuronal cells and oligodendrocytes are also able to synthesize cytokines [ 12, 421. Some cytokines are constitutively produced and released by glial cells [68]. Most of them are synthesized in response to different stimuli including bacterial lipopolysaccharides, viral antigens or cytokines themselves. Astrocytes can produce IL6 in respone to IL1 and TNFa as well as INFo@, GMCSF, G-CSF and TGFP2 [32, 501. Cytokine mRNA in cerebral structures can be detected using various techniques such as immunohistochemical analysis or in situ hybridization. ILlp immunoreactive fibers were identified in the human hypothalamus [9, 311 and significant expression of ILIP, IL6 and TGF-a mRNA were found in the rat hippocampus, hypothalamus and cerebral cortex [57]. With such technical analyses, it is difficult to ascertain whether endogenous cytokines are produced by cerebral cells or taken up from another tissue since meningeal and endothelial cells are also able to synthesize cytokines. There are conflicting points of view concerning the expression of cytgkines within the CNS. Some groups favour a well-defined regional distribution, as has been described for IL6 mRNA by Shobitz. In contrast, other authors consider it likely that cytokines are widely distributed within the brain [59]. Cytokines exert their biological activities via specific receptors. The different types of glial cells(microglia, astrocytes and oligodendrocytes) express the mRNA of the receptors for IL3 [21] IL4, IL6, IL7, GM-CSF and M-CSF [55]. However, at present only IL1 p and IL6 receptor mRNA have been studied in terms of their regional distribution in rat brain regions. They have been localised in the olfactory bulb, hippocampus, cerebral cortex and choroid plexus, but not in other regions [17]. The studies on IL1 and IL6 receptors specify a neuronal localization, and this
has led to a number of hypotheses concerning their possible physiological roles [3]. The messengers of cytokines and their corresponding receptors have been found to be co-expressed and co-localized with neurotransmitters and neurotrophic factors. The co-localization of NGF-mRNA and ILIP-mRNA has been analyzed throughout the adult rat brain [4]. Several studies have shown that IL1 could trigger the release of neurotransmitters such as somatostatin in rat brain cultures [56], and NGF from rat hippocampal cell cultures [20]. In addition, IL2 has been shown to play a potent role in acetylcholine release from hippocampal slices [25]. In functional terms, this may suggest an inter-relationship between the different types of soluble CNS factors. Many cytokines are expressed in cultured cerebral cells but only a few have been identified in the intact brain. In vitro they are mainly expressed after stimulation of the cells, and this observation may be related to their strong expression in response to CNS disorders.
Central
biological
activities
of cytokines
The effects of cytokines on nervous cells have been demonstrated in vitro. Several cytokines have neurotrophic activities. IL2, IL6 and TGFP promote neurite outgrowth and survival of primary cultured neurons such as neocortical neurons [60], septal cholinergic and catecholaminergic midbrain neurons [63] and dorsal root ganglia explants respectively [34]. They may influence the different stages of cerebral cell differentiation, and this has already been demonstrated for IL6 which induces the differentiation of rat PC12 cells into neuronal cells [54]. An effect of all the three isoforms of TGFP on neurite outgrowth and guidance was demonstrated in vivo after local injection into the brain [64]. Finally, cytokines such as IFNs (a/p, r) may retard the death of cultured rat sympathetic neurons caused by trophic factor deprivation and provide protection against natural cell death occurring to oligodendrocytes. Most of these neurotrophic activities are independent of the synthesis of neurotrophic factors as demonstrated by Tokiko [lo]. However, cytokines cannot be strictly considered as neurotrophic factors even though they share structural homologies with them [13]: the main difference is that whereas an essential part of the mechanism of action of neurotrophic factors is their retrograde transport to the neuronal
427 cell body, this phenomenon is not observed for cytokines. As mentioned above, this latter of molecules exerts its actions via specific receptors, and cytokine receptor binding induces a cascade of cellular signalling events such as prostaglandin synthesis [ 181. In addition to their neurotrophic roles, cytokines have a broad range of activities on multiple cell types. Some cytokines promote glial cell migration and proliferation (TNFa and ILl). Injection of IL1 into brain tissue stimulates astrogliosis, which is consistent with the enhanced proliferation of cultured astrocytes exposed to this cytokine [23]. Some cytokines modulate cell morphological changes [38], and activation of glial cells resulting, in part, in MHC antigen expression and growth factor production. Cytokines also regulate synaptic activities. In some circumstances they modify long term potentiation (TNF-alpha, ILlp) or regulate neuronal excitability [7]. They also increase synaptic transmission: IL2 can modulate K+ induced acetylcholine release from rat hippocampal and cortical slices [l]. However, recent studies argue that cytokines may not have direct synaptic effects on cerebral cells but modify neuronal excitability through nonspecific mechanisms [ 111. In addition, intracerebroventricular injection of INFol has been shown to alter neuronal firing rates in a number of brain regions [49]. With respect to these activities, cytokines may be considered as neuromodulators [62]. Cytokines exhibit functional interaction with other CNS factors: for example they may be regulated by neuropeptides such as Vasoactive Intestinal Peptide (VIP) which increases ILla mRNA and protein in rat cortical astrocytes [30], and they induce the synthesis and release of neuropeptides such as Corticotropin-Releasing-Factor [53]. Cytokines control the growth, differentiation and activation of cells in the CNS. Some of them have been identified at an early stage in the normal CNS (TGFol, TGFP, M-CSF) suggesting their participation in CNS ontogenesis. The range of biological activities described here emphasizes the in viva role of cytokines in the maintenance of CNS homeostasis.
CSF, exhibit pyrogenic activities. However, the pattern and duration of the fevers induced by these cytokines are distinct and their implications in fever production are ambiguous since cytokines can co-induce each other. They also act by separate mechanisms. The most well known endogenous pyrogen studied is ILlp. The mechanism of ILl-induced fever has been investigated: this includes, at least in part, eicosanoid synthesis and release of corticotropin releasing factor [51]. Accumulating evidence indicates that the regulatory centre of fever is located in the brain since intracerebral injection of IL1 requires a much lower concentration than its peripheral administration. Recent reports show that cytokines produced by cerebral cells modify behavioral functions including somnolence, anorexia and depressive activity. Such effects could be induced by systemic or intracerebra1 injections of recombinant cytokines: INF 01 or IL1 increase the duration of slow-wave sleep and modify its amplitude in a dose-dependent manner [8]. This activity of IL1 may be related to its expression in the hypothalamus, an area known to be involved in sleep regulation. IL1 and Macrophage inflammatory protein-l (MIP-1) has also been reported to induce anorexia, a time and dosedependent reduction of food motivated behavior and activation of the hypothalamo - pituitary - adrenal axis [39]. However, the same effects could be obtained by different routes of administration. For example, peripheral and central injections of IL1 induce fever and sickness behavior, including decreased food motivation and reduced interest in social activities. The use of an endogenous receptor antagonist, ILl-ra, has suggested that the receptor mechanisms which mediate the behavioral and pyrogenic effects of IL1 are heterogenous [2, 14, 271. The mechanisms underlying the behavioral effects of cytokines are poorly understood. Behavioral effects of cytokines are not exclusively dependent on a direct effect in the CNS, and the cytokine network is enlarged by interactions with hormones (ACTH, a-MSH), neurotransmitters and neuropeptides [33]. The question of whether the behavioral effects of cytokines are initiated in the periphery or in the central compartment, or both, remains to be elucidated.
Pyrogenic and behavioral actions of cytokines
Cytokines and disease
Infections and some injuries are often associated with fever. Several cytokines, including ILla@, IL2, IL6, IL8, TNFcx@, INFplr, MIP and GM-
It has been argued that the CNS is able to develop immune reactions since cytokines have been identified in multiple CNS pathologies including
428 inflammation and infection, trauma and neurodegenerative processes [67]. The orchestration of the wounding response is initiated by astrocytes and microglia, which are the main sources of cytokine synthesis. However, there are different points of view as to the first effector cells which trigger cellular and molecular events in the injured CNS. Some researchers emphasize that microglia, which represents the resident macrophages of the CNS, respond to immunological insult and injury to the brain and thus lead to astrocyte activation. However, astrocytes are also able to directly respond to bacterial lipopoltsaccharides or viral antigens, suggesting that they could initiate and propagate the immune central reaction via cytokine production. Whatever the central pathologies, microglia and astrocyte activation have been observed. This phenomenon represents a part of a cascade of events including cellular migration and proliferation as well as cytokine production. Concomitantly, there is an increase in receptors for these cytokines detected by in situ autoradiography [47]. Furthermore, glial cells play a role as antigen-presenting cells and exert different functions, for example as cytotoxic or phagocytic cells [44]. Infection CNS infection or, injury are associated with the recruitment of peripheral immune cells, predominantly or activated T cells as well as monocytes and macrophages. Cytokines increase capillary permeability, facilitating the migration of immune cells across the BBB. Blood peripheral mononuclear cells are recruited by local release of chemotactic cytokines such as the monocyte chemoattractant peptide 1 (MCPl) and macroinflammatory proteins (MIPI o! and @age MIPlP). These chemokines have been identified in astrocytic cell lines [37] and in vivo during brain inflammation. Cytokines participate in diverse CNS viral infections. They are implicated in Toxoplasma Gondii multiplication in human microglia [43], and Granulocyte Macrophage Colony Stimulation Factor is synthetized in human T-lymphotropic virus type I infected human glioma cells [41]. In addition, cytokine receptor genes have been found to be expressed in lymphocytic choriomeningitis [61]. During viral infections such as AIDS, cytokines may activate infiltrating B lymphocytes to secrete antiviral antibodies against cytopathic viruses.
Cytokines have been identified in several types of brain damage in response to mechanical or metabolic trauma. IL1 p mRNA has been shown to be increased in cerebral cortex after convulsions induced by kainic acid [35]. Central administration of ILl-ra markedly attenuates damage induced by focal cerebral ischemia or the pharmacological activation of NMDA receptors in the rat brain I.5 I], whereas TGF-PI prevents glutamate induced neurotoxicity in rat neocortical cultures. In support of their neurotrophic activity, cytokines may decrease the deleterious consequences of an excitotoxic or ischemic insult [46]. They play an important role in neuroprotection and represent interesting targets for the prevention of ischemic and excitotoxic brain damage [64].
Dysregulation of cytokine production may contribute to the establishment of neurodegenerative processes. The major pathological characteristic of multiple sclerosis (MS) is the demyelination of white matter. Microglial cells and mononuclear cell infiltrates are the main effector cells. They promote oligodendrocyte death and contribute to demyelination, at least in part, by the production of cytokines. ILl, TNFa, IFNy and TGFP were found in astrocytes surrounding multiple sclerosis plaques in human brain [26]. Their possible implication in this pathology is reinforced by in vitro studies, demonstrating that TNFor and IL2 are cytotoxic for oligodendrocytes [58]. The decline of cognitive functions observed in Alzheimer’s disease (AD) is characterized by a severe neuronal degenerescence of the septo-hippocampal pathway. The main characteristic of this pathology is the presence of neurofibrillary tangles and neuritic plaques. The latter are constituted by the deposition of P-amyloid protein. Recent studies report the overexpression of IL 1p, TNFc( and TGFPl mRNA in Alzheimer’s brain (151. Cytokines may have both beneficial and deleterious roles in the processes occurring in AD. Thus, for example, while a combination of cytokines seems to be required to induce amyloid deposition [40], an effect which possibly contributes to the production of AD, IL1 may help to”reduce the degenerative process by regulating NGF synthesis.
429 Like ILI, TNFa induces IL6 gene expression in astrocytes. These cytokines, possibly acting ilicr IL6, may induce an acute phase response in the brain 1521. If this hypothesis is confirmed, amyloidogenesis in AD and demyelination occurring in MS might be considered as inflammatory processes [66]. They might be orchestrated by intracerebral cytokines and acute phase proteins originating from glial cells, neurons or cells of the choroid plexus. The functional activation of microglia during inflammation and demyelination in the CNS may be influenced by a changing profile of cytokines as a pathology develops. Cytokines are implicated in CNS pathologies and form a complex network which could represent a new pharmacological target. However, one must take into account that stimulating as well as inhibitory effects of a similar cytokine have been described, for example for TGFPl in Alzheimer’s disease [ 151. Numerous unresolved questions remain regarding cytokine activation in the CNS. These include the neuroanatomical and neurochemical pathways involving in CNS wounding responses, and the precise roles of individual cytokines in inducing responses after CNS disorders.
Modulation of central nervous system disorders: potential therapeutic applications There is now considerable evidence that cytokines are important regulators of the injury response of the CNS and that modifications of their activities in damaged tissues can influence the wounding response beneficially. The analysis of the roles of cytokines within different inflammatory responses can provide insights into immune mechanisms of tissue damage, and provide a useful framework for developing strategies for therapeutic intervention [ 161. Several strategies for the modulation of CNS injury have been envisaged by the regulation of cytokine release and their actions: a) recombinant cytokines may be considered as therapeutical agents: intrathecal administration of IFNy has been tested in multiple sclerosis patients [24]; b) locally applied neutralizing anti-cytokine or anti-cytokine receptor antibodies reduce cytokine activity: this has been demonstrated for intracerebroventicular injection of ILI antibody which reduces its pyrogenic activity;
c) endogenous antagonists such as a sulfate proteoglycan which acts as a TGFP antagonist, could provide another therapeutical reagent [69]; d) the availability of the soluble receptor may provide another molecule capable of antagonizing endogenous cytokines within the injured CNS. An endogenous receptor antagonist peptide for ILI, termed IL1 ra, constitutively expressed in the hypothalamus [22], has been shown to be efficient in blocking ILIP actions on behavior or sleep after central administration [28]. ILI-ra may represent a potential therapeutic agent for reducing the neuronal degeneration associated with the excitotoxicity resulting from ischemia [48]. substantial problems Nevertheless, must be resolved before the intracerebral application of such proteins becomes a feasible therapeutic approach.
Conclusion Cytokines represent an important class of soluble factors in the CNS. They are synthesized by the different kinds of cerebral cells and participate in the maintenance of brain homeostasis as growth promoting and differentiating factors. They also exert activities at the synaptic level, which has led them to be considered as neuromodulators. Cytokines act in close inter-relationship with the other CNS soluble factors including neurotransmitters, neuropeptides and hormones. They play a pivotal role in modulating intracerebral immune responses: they are involved in the wounding response to diverse central disorders including infection, trauma and degenerative processes. The expression and regulation of cytokines and their corresponding receptors are the subject of intensive investigations, in that they represent potential pharmacological targets.
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