Cytokines and the nervous system II: actions and mechanisms of action

REVIEW Cytokines and the nervous system actions and mechanisms of action

II:

Nancy J. Rothwell and Stephen J. Hopkins Cytokines

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Trends Neurosci. (1995) 18, 130-136

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Nancy 1. Rothwell is at the School of Biological Sciences, Room 1.124, Stopford Building, University of Manchester, Manchester, UK Ml3 9PT, and Stephen J. Hopkins is at the University of Manchester Rheumatic Diseases Centre, Clinical Sciences Building, Hope Hospital, Salford, UK M6 8HD. 130

RECENT REVIEW in this journal’ reveals that many cytokines and their receptors are distributed widely in the PNS and the CNS, and their expression is influenced by changes in tissue homeostasis. These observations, together with the numerous and varied demonstrations of actions of cytokine on the nervous system or on neurones in vivo and in vitro, indicate that these molecules have important roles in neurobiology. Cytokine neurobiology is a relatively recent, and rapidly expanding, area of research that encompasses several scientific disciplines. This article presents a general overview of the subject but does not address all actions of cytokines on the nervous system, or consider specific methodological or scientific controversies in detail. It is inevitably incomplete, both by design and oversight, since there are over 2500 publications (Medline”) on cytokines and the nervous system. Well over half of these were published in the past two years, and additional information will certainly be available by the time of publication of this article. Specialized reviews exist on specific aspects of this field. For example, a number of excellent reviews describe the neurobiology of neurotrophins and related growth factors (see Refs 2-4) and, thus, these will be covered in less detail. An overview of actions of cytokines in the nervous system is presented in the accompanying poster. As with any emerging research topic, numerous effects of cytokines have been described. These can be divided broadly into three categories: interactions between cytokines and the PNS; effects of cytokines mediated via the CNS; and direct actions of cytokines on cells and tissues of the CNS. Interactions

between

cytokines

and the PNS

Although it is possible that cytokines act as physiological messengers between cells, most information has been derived from studies on tissue injury and inflammation. During the inflammatory response, the nervous system is involved in both perception and regulation of tissue activity. It is now clear that cytokines are involved in the neurogenic component of inflammation in addition to their TliVS Vol. 18, No. 3, 1995

established role in regulating inflammatory-cell, connective-tissue and vascular responses’ (Fig. 1). Increased synthesis of prostaglandins is a major feature of both acute and chronic inflammatory responses and is stimulated by a number of cytokines that are present at inflammatory sites, including interleukin 1 (IL-l), tumour necrosis factor (TNF), transforming growth factor p (TGF-l3) and platelet-derived growth factor (PDGF)‘. Unlike the rapid increases in production of eicosanoids, caused by mediators such as bradykinin, these cytokines primarily promote eicosanoid synthesis by inducing increased transcription of synthetic enzymes, including cyclooxygenase and phospholipase A,. One of the effects of prostaglandins (PGE, and PGI,) is to sensitize afferent pain fibres. Recent evidence suggests the involvement of cytokines, particularly IL-l and IL-6, in this hyperalgesic response, and that production of these cytokines is induced by bradykinin and TNF-a (see Ref. 6). The mechanism that underlies these actions is unclear, particularly with respect to IL-6 since, in contrast with other cytokines, IL-6 does not induce upregulation of enzymes that synthesize eicosanoids, although some of its actions within the CNS are antagonized by inhibitors of cyclooxygenase7)*. Despite the association of IL-l with hyperalgesia, an antinociceptive response is elicited when IL-l is injected intraperitoneally, an effect apparently mediated via the peripheral release and action of corticotrophin releasing hormone’ (CRH). The role of the sympathetic nervous system in pain and anti-inflammatory responses is unclear. However, the hyperalgesia induced by IL-S appears to be mediated via interaction with the sympathetic nervous system because its effects are inhibited by p-adrenoceptor antagonists”. Induction of both neural afferent and sympathetically mediated hyperalgesia apparently involves the release of TNF-(Y at an early stage”. In addition to the interaction between cytokines and neuropeptides in inflammatory lesions, cytokines regulate production of neuropeptides and neurotransmitters in damaged sympathetic neurones. These events could be related, since 0 1995, Elsevier Science Ltd

N. Rothwell

and S. Hopkins

- Cytokines

REVIEW

and the nervous system 11

C-fibre afferent Myelinated afferent

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Demyelination A

--I

PGs Substance P

5-HT Histamine

7 Macrophage

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Fibroblasts/endothelium

Fig. 1. Neural mediators and cytokine interactions in the inflammatory response. Potential activation signals generated by mediators that are released by neural offerent and sympathetic neurones and by other cells that are activated in inflamed tissues, are shown. Abbreviations: CGRP, calcitonin gene-related peptide; CNTF, ciliary neurotrophic factor; 5-HT, Shydroxytryptomine; IL, intedeukin; NA, noradrenaline; NCF, nerve growth factor; PCs, prostaglandins; TGF, transforming growth factor; and TNF, tumour necrosis factor.

changes in neuropeptide expression might be important in regulating the responses that are associated with defence and repair of both neuronal and nonneuronal tissue”. Although IL-l can induce these changes, it appears to act via induction of LIF (leukaemia inhibitory factor, Ref. 13), also known as cholinergic differentiation factor, which switches the synthesis of neurotransmitter from noradrenaline to ACh (Ref. 14) via induction of choline acetyltransferase. Other neuropoietic cytokines, particularly ciliary neurotrophic factor (CNTF), have similar effects, since their action is mediated by related receptors (see Ref. 1). Related patterns of gene transcription induced by LIF and CNTF have also been identified”, using molecular techniques that are likely to increase our understanding of how such cytokines regulate neuronal growth and function16. Cytokines (and particularly neurotrophins) have been implicated in responses to peripheral nerve injury, and many cytokines are induced locally after such insults’. Neurotrophins such as nerve growth

factor (NGF) promote the growth and survival of a variety of peripheral neuronal-cell types’. Although CNTF is not strictly a member of the neurotrophin family, it has, in common with other cytokines (IL-6 and LIF, see Ref. 1) binding to their distinct receptor family, similar activity to the neurotrophins. It acts as a survival factor for certain neurones, and a physiological role for CNTF in maintaining the function of normal adult motor neurones is supported by recent observations of motor-neurone degeneration in mice where expression of the CNTF gene was abolished by homologous recombination”. Thus, CNTF is under consideration as a potential treatment for certain neurodegenerative disorders. Other important growth factors include fibroblast growth factor (FGF), which can promote axonal regeneration”. A balanced interaction between neuronal and accessory cells during repair might be maintained via TGF-P, since this cytokine promotes Schwanncell growth and activity, while reducing NGF production19,20. TINS Vol. 18, No. 3, 1995

131

REVIEW

N. Rothwell

and 5. Hopkins

- Cytokines

and the nervous system II

Although the physiological function of cytokines might be to preserve or restore homeostasis, sustained or excessive production of cytokines can cause damage. Inflammatory cytokines, such as TNF-a, can result in demyelination and axonal degeneration directly’l, and might thereby contribute to the neuropathies that are associated with diseases such as leprosy and Chagas’ disease”. Many cytokines affect CNS function when administered systemically. Resolution of the question of which effects are important physiologically revolves largely around identifying the nature, location and timecourse of synthesis in the periphery, and where and whether they enter the CNS. This controversy is discussed in an earlier review’, particularly in the context of fever and hypothalamic-pituitary-adrenal axis (HPA) activation, which are the major areas of research that have addressed this question. One possible mechanism of activation of the CNS by peripheral cytokines would be via stimulation of peripheral neural afferents. Peripheral injection of IL-1 stimulates release of noradrenaline in the hypothalamus, and it has been suggested that this in turn stimulates release of CRH, which mediates some activities of IL-1 (Refs 7 and 23-25). Activation of neural afferents might result in secondary induction of cytokines within the CNS, and might also explain the induction of IL-l within the hypothalamus by peripheral pyrogens (see Ref. 1). Although the mechanisms by which peripherally released cytokines induce fever is unclear, their effects apparently involve activation of the hypothalamus and, in most cases, synthesis of prostaglandins (see below). Cytokine

actions

in the brain

Actions that influence peripheral fimctions

Fever, altered neuroendocrine, cardiovascular and gastric function, increased metabolism, behavioural anorexia, somnolence, changes (for example, reduced exploratory and sexual activity), acute-phase protein production and activation of the immune system are characteristic host responses to systemic infection, injury and inflammation. Most of these responses can be mimicked by peripheral or central injection of cytokines (see Ref. 29, although they are much more effective when injected into the brain7,2s,26.For example, in the rat, intracerebroventricular or intracerebral injection of 100 pg-10 ng of IL-lp elicits maximal changes in many of the systemic responses described above, whereas intravenous doses of several micrograms are usually required to mimic these effects. These observations indicate that cytokines can modulate systemic functions by direct actions on the brain. More direct evidence for this proposal derives from studies in which actions of cytoklnes in the brain have been inhibited experimentally. These studies have been enhanced by the discovery of a naturally occurring ILl-receptor antagonistz7 (IL-lra), which is not only a useful experimental tool, but is also a fascinating endogenous inhibitor of the action of IL-l, and is present in normal brain=. Central injection of IL-lra inhibits HPA-axis activation, sleep and behavioural changes elicited by systemic administration of endotoxin or muramyl dipeptide (both of which release cytokines) in rodentsz5. Inhibition of the action of cytokines has also been achieved by injection of antibodies 132

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that ‘neutralize’ the cytokine or its receptor. For example, central injection of antibodies to IL-lp or IL-6 attenuates fever and thermogenesis induced by endotoxin7,29. The development of antisense oligonucleotides to block expression of cytokines or their receptors might prove particularly valuable in elucidating the function of these molecules in the nervous system. Pyrogenic responses to central injection of most cytokines have been ascribed to release of prostaglandins (PGs), particularly PGE, and PGF, (Refs 30 and 31), the synthesis of which can be induced by administration of cytoklnes within the preoptic or anterior hypothalamus and in the vascular organ lamina terminalis3’f31 (OVLT). However, where PGs are involved in the pathway is unclear. Interleukin-1 and TNF induce expression of cyclooxygenase and phospholipase A,. However, IL-6 has not been shown convincingly to increase the synthesis of PGs directly in any cell type, although the central or peripheral injection of IL-6 increases the concentration of PGE, in the cerebrospinal fluid (CSF), and this is prevented by inhibitors of cyclooxygenase3’. Therefore, it seems likely that IL-6 induces a secondary mediator with PGinducing activity. More recently it has been demonstrated that certain cytokines (IL-lp, IL-6 and IL-8) elicit fever and thermogenesis via release of CRH, whereas others (IL-la and TNF-a) act independently of CRH (Refs 7 and 33). The relationships between cytokines, PGs and CRH are complex. Central actions of CRH are not modified by inhibitors of cyclooxygenase, but PGFzUreportedly stimulates release of CRH, and central effects of PGFzO(but not PGE,) on fever are prevented by blocking the action of CRH (Ref. 33). These data suggest that specific PGs might induce release of CRH, and mediate the actions of certain cytokines. The exception to this requirement for induction of PGs is the chemokines IL-8 and macrophage inflammatory protein lc~ (MIP-lu) which, in the rat, induce fever that is not inhibited by inhibitors of cyclooxygenase34,“5, although they effectively inhibit IL-&induced fever in the rabbit (G. De Souza, pers. commun.). Thus, several distinct pathways for the induction of fever, and associated increases in thermogenesis, might exist within the brain7rz5. Further complexity is added by data that suggest that fever that results from systemic or central administration of IL-1 depends on different mechanisms, with only the latter involving release of CRH in brain36. Cytokines influence many neuroendocrine systems, the most prominent of which is activation of the HPA axis, resulting in release of adrenocorticotrophic hormone (ACTH) and glucocorticoids37. Interleukin-1 is one of the most potent activators of the HPA axis, but other cytokines, such as IL-2, IL-6 and TNF-a, can affect neuroendocrine responses and act synergistically with IL-l (Ref. 37). Peripheral or central administration of IL-lp or IL-6 causes release of CRH which, subsequently, stimulates release of ACTH and glucocorticoids, although cytokines can exert direct effects at the level of the pituitary and the adrenal glands37,3*.Although effects on the hypothalamic-pituitary-gonadal axis have received rather less attention, recent experiments suggest that chronic administration of IL-ll3 into the CNS disrupts the oestrous cycle by inhibiting the synthesis and release of leuteinizing hormone releasing

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hormone (LHRH), and inhibits luteolysis via increased production of prolactir?‘. Central effects of cytokines on the HPA axis involve synthesis of prostaglandins, indicating that common mechanisms might be responsible for the neuroendocrine and febrile actions described above. Corticotrophin releasing factor has also been implicated in centrally mediated antinociceptive and cardiovascular actions of IL-1 (Refs 9 and 36), and in suppression of peripheral immune function40. In these cases, CRH apparently acts independently of pituitary-adrenal stimulation. In contrast, modification of behaviour (for example, appetite, avoidance behaviour and sleep) by cytokines can be dissociated from effects on fever and HPA-axis activity. Cytokines suppress appetite and elicit ‘sickness behaviour’ by central actions that involve PGs, but the role of CRH in behavioural responses to IL-1 is controversial. There is also some evidence that different IL-l receptors might be involved in fever and behavioural responses. In the same protocol in the rat, central injection of IL-lra inhibits changes in behaviour, but not fever or thermogenesis, elicited by central administration of IL-1 (Ref. 41). Increased slow-wave sleep can be induced in the rat by central injection of IL-l, TNF-a, IFN-a or FGF, but not by IL-6, and it has been proposed that cytokines are also involved in the physiological regulation of sleep, even in the absence of disease or injury42,43. Although IL-2 and IL-3 have been reported to induce sleep44, the biological importance of this is obscure. Somnogenic responses to IL-l are not dependent on PGs or CRH (although CRH might be involved in behavioural activation elicited by cytokines) and can be dissociated from fever4’. Furthermore, inhibition of activity of nitric oxide synthase attenuates somnogenic effects of cytokines without affecting fever45. Cytokines can also elicit sedation and EEG synchronization, and changes in EEG activity elicited by cytokines have been ascribed to effects on the locus coeruleus45. In contrast, higher doses of these cytokines can elicit epileptogenie activity, particularly when injected into the hippocampus4’. Cytokines can also influence peripheral immune function via direct effects on the brain. Central administration of IL-l causes marked increases in circulating concentrations of IL-6 (Ref. 46), and inhibition of the activity of natural killer cells in the periphery4’, both of which are dependent on activation of the sympathetic nervous system. Indeed, several central actions of cytokines on systemic function result from alterations in ANS activity, including fever, hypermetabolism, gastric function, bowel activity, cardiovascular and immune effects. However, these central actions appear to depend on multiple mechanisms, since inhibition of immune activation4’, but not stimulation of systemic release of IL-6 (Ref. 46), is dependent on CRH. The demonstration that very small quantities of cytokines in the brain can influence systemic immune responses and peripheral cytokine synthesis profoundly has required a major revision in our understanding of responses to tissue damage, and has provided some scientific basis for suggestions (once considered by many as anecdotal) that stress or psychological disturbance can influence responses to disease.

N. Rothwell

and S. Hopkins

- Cytokines

REVIEW

and the nervous system II

Early studies indicated that common mechanisms might be involved in the numerous actions of cytokines in the brain, and indeed PGs and CRH have been implicated in several effects of IL-l in the brain (see Refs 7 and 25). However, even the brief summary above reveals some important differences in the mechanisms of action of cytoklnes, and several studies have clearly dissociated mediators and pathways that are involved in the actions of IL-1 on specific host-defence responses. It must, therefore, be assumed that this diversity reflects multiple sites of action or involvement of different receptor subtypes, or both (see Ref. 1). Actions on brain function

Cytokines have been reported to influence many central neurotransmitters, including noradrenaline, 5-HT, GABA and ACh, and expression of a number of neuropeptides [for example, CRH, somatostatin, substance P, opioids, cholecystokinin and vasoactive intestinal peptide (VIP)] in several brain regions’5,25,47. However, the interrelationships between each of these varied responses of the neurotransmitters, and their relevance to specific cytokine actions have yet to be defined. Similarly, a number of second messenger systems in neurones are affected by cytokines, including activation of CAMP, activity of protein kinase C, synthesis of nitric oxide, release of arachidonic acid and Ca” flux. Indeed, almost all known intracellular signal-transduction mechanisms have, at some time, been implicated in cytokine actions, but with a few exceptions these have not been related to specific responses. Several cytokines have been reported to affect neuronal differentiation and growth4* and modify synaptic plasticity acutely in brain slice preparations. Interleukin-lp, IL-2, TNF-a, IFN-p and IFN-cx all inhibit long-term potentiation (LTP), although these effects probably do not share common mechanisms since the timecourse and nature of inhibition varies for each cytokine 41,48.In contrast, epidermal growth factor (EGF) and NGF enhance potentiation of the population spike amplitude and inhibit LTP in dentate gyms in vivo48. The mechanisms of these effects are unknown, but IL-l increases the effect of GABA by enhancing conductance of Cl- (Ref. 49), and inhibits Ca” currents in hippocampal neurones”, both of which might lead to inhibition of LTP. However, IL-1 also causes release of nitric oxide and arachidonic acid, which might enhance LTP, perhaps at higher concentrations of the cytokine’l. Neurotoxic concentrations of excitatory amino acids (EAAs) or EAA-receptor agonists induce expression of IL-1 in brain’, but no published data are available on effects of ‘physiological’ (subtoxic) doses of EAAs, or induction of LTP on cytokine synthesis, or on the role of endogenous cytokines in synaptic plasticity. Probably the most extensively studied, but no less controversial and complex, actions of cytokines on the CNS are on neuronal growth, differentiation and survival, and this topic has been studied largely in isolation from research on actions of cytokines on peripheral-nerve repair. Similar mechanisms appear to be involved in regulating lineage commitment and cellular differentiation in the neural and haematopoietic systems, and IL-5, IL-7, IL-9 and IL-1 1 can influence development of ion channels and action potentials in cultured brain neurones48,52,53. TINS Vol. 18, No. 3, 1995

133

Box

I. Cytokines

and neurological

Increased concentrations of a variety of cytokines have been observed in brain and cerebrospinal fluid in neurological disease. Crucial questions are whether these cytokines are causal in the disease process or secondary to cell damage, what role they play in responses to the disease and, perhaps most importantly, whether they exert beneficial or detrimental effects. Several growth factors that are overexpressed after brain damage clearly support the survival of neurones in culturebd, and some have been shown to inhibit ischaemic and excitotoxic damage in vivo or in vitro [for example, transforming growth factor p (TGF-I3) and fibroblast growth factor (FGF) (Refs c-e). In most cases, the mechanisms of these effects have not been identified, although the recent observation that FGF regulates expression of a functional NMDA receptor’ is an important advance in this field. However, for many cytokines, conflicting data exist, indicating that many can exert neurotrophic, neuroprotective and neurotoxic actions. For example, the cytokine interleukin 6 (IL-6) promotes neuronal survival, and inhibits NMDA toxicity8 and ischaemic damage in vivo (R. Le Feuvre, J. Relton and N.J. Rothwell, unpublished observations), but transgenic mice overexpressing IL-6 in astrocytes show marked neurodegenerationh, and there is evidence to suggest that growth factors, particularly TGF-l3 and FGF, promote scar formation which can hinder functional recovery after brain injury’. Similarly, IL-1 has been proposed to promote repair from neuronal damager, and is protective at low concentrations in v&ok. In contrast, IL-1 can also exhibit neurotoxicityk, and infusion of IL-1 into the brain of rats leads to glial-cell activation and neuronal loss’. Marked increases in expression of IL-l, IL-6 and TNF-a have been observed in rats within 6-8 h after brain damagem, and mRNA for IL-lp is induced within 15 min of forebrain ischaemia in the rat”. This very rapid expression precedes invasion of peripheral immune cells, and might originate from injured neurones, microglia or perivascular cells. More importantly, inhibition of action of IL-l, by central injection of ILl-receptor antagonists (IL-lra), markedly inhibits neurodegeneration induced by focal cerebral ischaemia (Fig.) or activation of excitatory amino acid receptors in the rat brain”. These data indicate that, in vivo, endogenous IL-1 participates directly in neurodegeneration. Similarly, trophic and toxic effects of IL-3 and IL-6 have been reported in neuronal cultures under different conditions k,“. The brain has been considered an ‘immune-privileged site’, but can produce molecules, such as acute-phase proteins, complement factors, antigen-presenting cells and phagocytic cells, and processes that are associated classically with peripheral immune functionr-‘. Microglia, which are activated by cytokines, function as phagocytic cells which can engulf neuronesh. Interleukin-1 induces expression of complement and acute-phase proteins such as p-amyloid precursor protein (p-APP), a-antichymotrypsin and adhesion molecules’, while interferon y

Various cytokines (IL-4, IL-6, IL-7, IL-8, TNF-(r, LIF and CNTF) enhance cell survival or growth of cultured neurones, or both, while others can exert both neurotrophic and neurotoxic effects, usually

depending on their concentration (for example, IL-l, IL-3 and TNF-IX)51,54.In neuronal cultures, low concentrations of IL-1 protect against excitotoxic damage, apparently by release of NGF (P. Strijbos and N.J. Rothwell, unpublished observations), and are neurotrophic, whereas higher concentrations are 134

Tlh5 Vol. 18, No. 3, 1995

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E” = 60 B s ‘fj=J 40 3

disease

L

I

** L -L

Contr '01 MK801

**

Contr '01 IL-l ra

Fig. Comparisonof the neuroprotective effects of MK801 and (IL- 1ra). Histograms show mean infarct volume (* SEM) determined histologically in rats 24 h after focal ischaemia (middle-cerebralartery occlusion). Animals were injected with appropriate vehicle (control), dizocilpine (MK801) (1 mgkq’ sub. cut.) 30min before, or interleokin J receptor antagonist (IL- I ra) (10 pg into the lateral cerebral vehicle), 30 min before and 10 min after ischoemia. (S. L. Loddick and IV.]. Rothwell, unpublished observations.) **: P
(IFN-y) and tumour necrosis factor (Y (TNF-CX) causes expression of monohistocompatibility complex (MHC)‘. The mechanisms of these neurotoxic effects of IL-l, and its involvement in ischaemic and excitotoxic damage, are largely unknown. These appear to be independent of effects on body temperature, at least in focal ischaemia, but might share some common mechanisms with actions of IL-l on other parameters (see main text), such as dependence on corticotrophin releasing hormone (CRH) and inhibition by the phospholipid-binding protein, lipocortin-1 (Ref. 0). In addition to effects on neurones and glia, cytokines can influence CNS function indirectly, for example by disruption of the blood-brain barrier, induction of synthesis of nitric oxide in endothelial cells, and facilitation of the entry of circulating immune cell9~‘. Interleukin 1 has also been implicated in neurological symptoms of HIV (human immunodeficiency virus) infection. It is induced by gp120, the viral envelope coat protein of HIV (Ref. t), and in Alzheimer’s diseaser,“. Increased synthesis of IL-l and IL-6 in the plaques of patients with Alzheimer’s disease and Down syndrome has been reportedvaw. Interleukin 1 and TGF-p are potent inducers of synthesis of P-APP (Ref. x), which is now considered fundamental to the disease. Head injury is an important risk factor for Alzheimer’s diseaser, and injury induces expression of IL-l, TGF-I3 and p-APP (see main text). Thus, IL-l (and perhaps other cytokines) might be a causal factor in the development of Alzheimer’s disease in

neurotoxics4f155.In vivo, IL-1 has been implicated in the neurodegeneration that results from cerebral ischaemia or overactivation of EAA receptorsS1 (see Box 1). Neuronal function can also be influenced directly by glia, which are an important source and locus of action of many cytokines in the brain. Bacterial endotoxin and cytokines, such as IL-l, TNF-(r, interferon-y (IFN-j) and macrophage colony stimulating factor (MCSF), stimulate the production of both themselves,

N.RothwellandS.

response to immune activation or brain traumaP,“, but this hypothesis requires further investigation. Overexpression of numerous cytokines has been reported in multiple sclerosis (MS) and in experimental allergic encephalomyelitis (EAE) in the raty. In particular TNF-a, which is toxic to oligodendrocytes and causes demyelination’, and IFN-?I, which causes macrophage activation and MHC Class II expression, have been proposed as causal factors in this diseaseY+“. Inhibition of action of IL-1 action by central injection of a soluble IL-1 receptor delays the symptoms of EAE (Ref. bb). In addition to the effects of cytokines on neuronal survival and damage, behaviour and neuroendocrine function, recent reports of their induction by stress indicate possible roles for these molecules in other forms of neurological disease, such as depression and aberrant behavlours. Thus, modification of cytokine synthesis or action might prove a valuable area for future therapeutic intervention. References a h c d e f g h

Eide, F.F., Lowenstein, D.H. and Reichard, L.F. (1993) Exp. Neural. 121,200-214 Finklestein. S.P. et al. (1990) Stroke 21, 122-124 Mattson, G.P. (1990) kdv. Eip. Med. Biol. 268, 211-220 Unsicker, K. et al. (1992) Curr. Opin. Neural. 2, 671-678 Pren, J.H.M., Backhauss, C. and Krieglstein, J. (1993) J. Cereb. Blood Flow Metub. 13, 521-525 Mattson. M.P. et al. (1993) 1. Neurosci. 13. 4575-4588 Toulmond, S. et al. (1992j Neuroscience L&. 144, 49-96 Camnbell, I.L. et al. (1993) Proc. Natl Acad. Sci. USA 90, 10061-10065

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Logan, A. and Berry, M. (1993) Trends Pharmacol. Sci. 14, 337-343 Giulian, D. and Tapscott, M. (1988) Brain BehaL. ImmunoZ. 2,3X!-358 Arauio, D.M. (19921 in Treatment of Dernentias (Maver. . .

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Bourdiol, F. et al. (1991) Bruin Res. 543, 194-200 Taupin, V. et al. (1993) ;. Neuroimmunol. 42, 177-186 Minami, M. et al. (1992) 1. Neurochem. 58, 390-392 Rothwell, NJ. and Relton, J.K. (1993) Neurosci. Biobehav. Rev. 17,217-227 Royston, M.C., Rothwell, N.J. and Roberts, G.W. (1992) Trends Pharmacol. Sci. 13, 131-133 Araujo, D.M. and Colman, C.W. (1993) Bruin Res. 600, 49-55 Berkenbosch, F., Robakis, N. and Blum, M. (1991) in Peripheral SignalZing of the Brain (Frederickson, R.C.A.,

McGaugh, J.L. and Felten, D.L., eds), pp. 131-145, Hogrefe & Huber Beneviste. E. (1992) in Neuroimmunoendocrinoloav (Blalock. J.E., ed.), vol. i2, pi. 106-153, Karger -’ Lipton, S.A. (1992) Trends Neurosci. 15, 75-79 Vandenabeele,

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Merrill, J.E. et al. (1992) Proc. NuN Acad. Sci. USA 89, 574-578 Louis, J-C. et al. (1993) Science 259, 689-692 Panitch, H. (1992) Drugs 44,946-961 Beneviste, E. (1992) Am. I. Physiol. 263, Cl-Cl6

other cytokines by astrocytes and microglia and increase glial growth 56~57 . Glial-cell development is also regulated by cytokines. Neurotrophin-3 and PDGF have recently been shown to synergize in promoting oligodendrocyte development’*. In contrast, TNF-cx is toxic to oligodendrocytes, an effect that is inhibited by CNTF (Ref. 59). This might be relevant to multiple sclerosis since, as in the periphery, increased expression of TNF-a in brain has been associated with demyelination. A fascinating observation, that requires

H~~kins-Cytokinesandthenervous

REVIEW

system II

further investigation, is the significant sequence homology between molecules that are associated with programmed cell death and those that are related to production or action of cytokines. Ced-3, a gene product which appears to be responsible for apoptosis in the nematbde Caenorhabditis elegans, shares significant sequence homology with interleukin-lp converting enzyme (ICE, which cleaves pro-IL-lp intracellularly) 6o. The relevance of these findings to neuronal cell death is not clear, but amA, a gene product which inhibits ICE, prevents neuronal death in chick dorsal-root ganglion neurones61. It is not certain whether the potential involvement of ICE (or related enzymes) in neuronal death, suggested by these observations, is due to its actions on release of IL-l or to another effect of the enzyme. Nevertheless, there is currently great excitement about the role of ICE in neurodegenerative disease, and its potential as a therapeutic target. The Fas/Apo-1 cell-surface receptors and their ligand(s), which are involved in programmed cell death in a variety of cell types, also show strong homology with both TNF receptor subtype@‘. Inhibition

of cytokine

action

Since overproduction of cytokines can lead to tissue damage, it is not surprising that there are a number of endogenous molecules and mechanisms that inhibit cytokine systems or action. One of the most interesting of these, IL-lra, is present in peripheral and brain tissuesz8, and inhibits many of the central actions of IL-1 (Ref. 25), although its normal function in the CNS has not been identified. There appear to be few examples of naturally occurring competitive antagonists, although a product of alternate FGF mRNA splicing acts to antagonize FGF acutely63. Glucocorticoids are potent inhibitors of central, as well as peripheral, synthesis and actions of cytokines. Some of these effects appear to be mediated by the phospholipid-binding protein, lipocortin-1, which inhibits inflammation, fever, pituitaryadrenal activation and neurodegeneration, probably via inhibition of release of CRH (Ref. 64). cu-Melanocyte stimulating hormone (aMSH) and vasopressin also attenuate actions of cytokines in the brain65, and these peptides, as well as lipocortin, have been implicated in impaired febrile responses to cytokines in ageing animals. The opposing actions of certain cytokines might be of clinical benefit. For example, IFN-P inhibits the clinical symptoms of multiple sclerosis, probably by blocking release or actions of IFN-y (Ref. 66), and both IL-4 and IL-10 can downregulate induction of IL-1 (Refs 67 and 68). A variety of therapeutic interventions has been developed in an attempt to suppress cytokine synthesis or actions, predominantly for use in systemic diseases, but many of these are also likely to be effective on the nervous system. Actions of cytokines that are dependent on synthesis of eicosanoids can be modulated by glucocorticoids, inhibitors of cyclooxygenase, and dietary fatty-acid modification. For example, supplementation of rats with omega-3 fatty acids inhibits central as well as peripheral effects of IL-l on fever69, and reduces neuronal damage caused by focal ischaemia or NMDA-receptor activation7’. The methylxanthine pentoxifylline reduces activation of inflammatory cells by a variety of stimuli, including TNF and IL-l, and selectively reduces TINS Vol. 18, No. 3, 1995

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REVIEW

N.Rothwell

and S.Hopkins-Cytokines

and the nervoussystem

II

induction of TNFa, but not IL-lfi, in vitr~~~,~~. It also inhibits expression of TNF-a during lipopolysaccharideinduced fever73 and the inflammation in allergic encephalomyelitis74. These effects appear to be mediated primarily via inhibition of phosphodiesterase, and a consequent increase in the concentration of CAMP. Concluding

remarks

The study of actions of cytokines on the nervous system is in its infancy, but has already revealed diverse effects of these molecules on many aspects of neuronal function. While these molecules have been implicated in many disease states, their role in normal physiology is largely unknown. Increased concentrations of tissue or circulating cytokines during exercise, pregnancy and stress suggest that they might affect homeostatic function, but the most direct evidence for their physiological importance relates to their effects on normal sleep patterns. The relevance of cytokine actions to a variety of neurological disorders is now being determined, and has opened a potentially fruitful area of research and therapeutic development. However, available data indicate a complex picture, with many cytoklnes exerting opposing actions, depending on their concentration, site and duration of action, and the presence of other cytokines or related molecules. It appears that cytokines have several, probably distinct, actions on the nervous system: as communicators to the brain of systemic injury, infection and inflammation; as modulators of responses to peripheralnerve injury; as neuromodulators (and possibly neurotransmitters) of the CNS control of systemic host defence responses to disease and injury; and as molecules that inhibit or mediate neurodegeneration and repair in the brain. The diversity and complexity of these actions is overwhelming. However, given their number and varied actions, and the relatively recent discovery of cytoklnes, such apparent confusion is perhaps to be expected. In this context, it is important to note that few investigations have taken into account the biological activity of cytokine preparations, or the relevance of doses and sites of injection to endogen-ous synthesis of cytokines. Nevertheless, the indications to date are that cytokines will emerge as a group of molecules with actions and roles in neurobiology that are as significant as those of known neuropeptides. It is now essential to identify not only those cytokines and their actions that are associated directly with physiological regulation and disease processes, but also their mechanisms of action. A clear understanding of these processes, combined with development of methods to manipulate them, is likely to offer significant therapeutic potential in the control of diseases involving the nervous system. Selected references 1 Honkins, S.J. and Rothwell, NJ. (1994) Trends Neurosci. 18,83-88 2 Eide, F.F., iowenstein, D:H. and Reichardt, L.F. (1993) Exp. Neural. 121, 200-214 3 Korsching, S. (1993) 1. Neuroscience 13, 2739-2748 4 Mattson. M.P. (1990) Adv. EXD. Med. Biol. 268. 21 I-220 5 Hopkins, S.J. (i990) Ann. R&m. Dis. 49, ZOY-211 6 Dray, A. and Bevan, S. (1993) Trends Pharmacol. Sci. 14, 287-290 7 Rothwell, N.J. (1991) Trends Pharmacol. Sci. 12, 430-436 8 Dinarello, CA. et al. (1991) Brain Res. 562, 199-206 9 Kita, A., Imano, K. and Nakamura, H. (1993) Eur. J. Pharnmcol. 237, 317-322 10 Cunha, F.Q. et al. (1991) Br. J. Phamacol. 104, 765-767 11 Cunha, F.Q. et al. (1992) Br. J. Pharmacol. 107, 660-664 12 Patterson, P.H. (1993) C.R. Acad. Sci. Ser. III 316, 1150-1157

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