Cytokines and the nervous system I: expression and recognition

Cytokines and the nervous system I: expression and recognition Stephen J. Hopkins and Nancy J. Rothwell Cytokines are a heterogeneous group of polypeptide mediators that have been aswciakd classicallywlth activation of the lmmune system and inflammatory responses.An incmasing number of related mediators is now included in this category and most of them have been shown to act on a variety of tissues, including the PNS and CNS. Cytokines and their recep

tars are expressed in tissues of these nervous systems, and might derive from invading immune, or resident, cells. Trauma in peripheral tissuesmight also induce cytoklne-mediated events in the CNS, via either the circulation or secondary lnductlon wlthin the brain, In this first of

a two=part review, the general properties, expression and recognition of these

cytoklneswith respect to the nervous system are discussed. TtrrtdsNetrrosci. (1995) 18,83-88

HE NERVOUS and endocrine systems have wellestablished roles in the maintenance of systemic T homeostasis. The integrity of individual tissues is, however, malntained largely by a third, and almost certainly older, mechanism that involves the production of a variety of cellular mediators that are known as cytoldnes (Table 1). Although the boundaries between different regulatory mtdiators are somewhat blurred, cytokines can be characterized generally as polypeptide hormones that regulate homeostasis in the tissue of origin, either via local actions or by recruitment of external systems that facilitate restoration of local homeostasis. With few exceptions [for example, macrophage colony stimulating factor (M-CSF), which might also function as a classical endocrine hormone], their extracellular expression in normal adult tissues as biologtcally active mediators is extremely low, or absent (that is, close to the detection limits of even the most sensitive assays). This contrasts with mediators in the ner. vous and conventional endocrine systems, which demonstrably have important roles under equilib. rium conditions. Expression and activity of cytoktnes is increased in conditions of tlssue ‘stress’, which might include phases of rapid growth (for example, embryogenesis and tissue repair), tissue dysregulation (for example, chronic inflammatory disease and tumour growth), infection and trauma. Reiatlvely minor or moderate insults to tissue integrity induce production of a variety of cytokines that act locally, in a paracrine or autocrine manner. However, a few cytokines [for example, interleukin 6 (IL-6) and the CSR] appear to exert at least part of their tissue function by entering the cbculation, where they recruit systemic responses that are important for maintaining the integrity of the injured tissue (for example, acute phase response, haemopoiesis and glucocorticoid induction). This controlled or acute production, or both, of cytokines exerts an important regulatory function, promotmg growth and differentiation, or defence and repair, of tissues. In situation!, where 8 1995. Elrevler Scicnm

Ltd 0166 - 2236/9S/SKW~~

there is extreme tissue trauma or systemic insult,

those cytokines that are usually restricted to the tissaes might enter the ctrculation. This, and the chronic production of cytokines within tissues, can result in a threat to systemic or local homeostasis, and has been implicated in numerous pathological conditions. Although there is some evidence for the action of cytokines in ‘normal’ physiological events, such as exercise, psychological stress and even sleep, their role in these situations is more controversial. A general feature of cytokines is the extremely broad range of activities that they exhibit, the extent to which their activities overlap, and the wide range of cells that is able to produce several cytokines. This has contributed to the difficulty in identifying physiological roles for cytokines. Identification of function within the nervous system is no exception, since it is clear that the nervous system and Its associated cells can both pm&ice and respond to many cytoldnes. To some extent this is owing to the fact that ‘cytoktne’ is now used as an umbrella term for an increasing number of mediator families. Although there is some debate as to whether all of the factors included in Tdble 1 should be defined as cytokines, there is little reason to distinguish between their general properties and hmctions. The descriptive value of the names for individual cytokines and their families is becoming increasingly redundant, and many cytokines either are. or could be, included in more than one of the families. The source and target tissues that defined their activities originally also overlap considerably, and members of each of the cytokine families can certainly influence the nervous system, as well as regulate the fundion of mflammatory and immune ceils. Since all cells produce and respond to at least some, and normally several, cytokines. the inter-relationships and Carltrol mechanisms are potentially complex. ldentiftcation of the sites of expression, and factors that control expression is, therefore. an im;*ortant element in understanding how these mediators function. 83

Family

Members

Major activities and features

lnterleukins

IL-lo, IL-I B. ILira and IL-24L-I5

Multiple tissue and lmunoreguiatory activities; no similarity of activity is implled by membership of this family

Chemokines

IL-8/NAP-I, NAP-2, MIP- I (Yand B, MCAFlMCP-I, PIGSA and BANTES

Leukocyte chemotaxls and cellular activation

Tumour necrosis factors

TNF-o and TNF-B

Similar to IL-I, in addition to tumour cytotoxiclry

interferons

IFN-a, B and y

inhibltlon of Intracellular viral replication and ceil growth regulation; IFN-y is primarily lmmunoregulatory

Colony stimulating factors

G-CSF, M-CSF, GM-CSF, IL-3 and some of the other ILs

Colony ceil formatton in the bone marrow

Grcwth factors

EGF, FGF, PDGF. TGF-ct, TGF-B and ECGF

Ceil growth and differentiation

Neurotrophins

BDNF, NGF, NT-3-NT-6

Growth

Neuropoietins

LIF, CNTF, GM and IL-6

and GDNF

and

activation

of mature leukocytefunctions

and differentiation of neurones

Cytoklnes acting on the nervous system, and acting via a related receptor complex

Abbreviations: BDNF, brain-derived neurotrophlc factor; CNTF, clliary neurotrophlc factor: EGF, epldermal growth factor: ECGF, endothellal cell growth factor; FGF, flbroblast growth factor; GDNF, gllal-derived neurotrophlc factor: G, M and GMCSF, granulocyte, macrophage and grantdocytelmacrophage colony stimulating factor(s): IFN, Interferon; IL, Interleukin; IL-lra, Interleukin-I receptor antsgonlst; MCAF, monocyre chemotac. tic and activating factor; MCP, monocyte chemotactic protein; MGSA, melanoma growth stlmulatory actlvlty; MIP, macrophage inflammatory protein; NGF, nerve growth factor; Nr, neurotrophin; NAP, neutrophll activating protein: OM, oncortatin M: PDGF, platelet-derived growth factor: RANT&, regulated upon activation normal expressed and secreted; TGF, transforming growth factor: and TNF, tumour necrosis f&or.

Cytokine expression in the PNS

Following nerve and tissue injury, infiltrating leukocytes produce a variety of cytokines that are characteristic of the inflammatory response, including IL-l, IL-6, tumour necrosis factor oi (TNF-(u)and transforming growth factor p (TGF-B). The nervous system can itself promote production of these cytokines during the inflammatory response. Activation of sensory afferent fibres induces antidromic release of a number of inflammatory neuropeptides, including substance P and calcitonin gene-related peptide (CGRP), which can induce production of inflammatory cytokines by macrophages and mast cells’-“. Following stimulation of sympathetic nerves, activation of p-adrenoceptors induces production of IL-6 (Ref. 4). This is mimicked by systemic administration of adrenaline’. In addition to contributing to the release of IL-6 during tissue trauma, this mechanism could explain the increase in the plasma concentration of IL-6 that is observed following psychological stres9. Cytokines that are associated with inflammation can, in turn, induce synthesis and release of a variety of other cytokines that are capable of promoting the survival and repair of nerve tissue. For example, IL-1 induces production of leukaemia inhibitory factor (LIF; also termed cholinergic differentiation factor) in sympathetic ganglia’, and both IL-1 and TNF induce production of nerve growth factor (NGF) in nerve tissueR.y, as well as stimulating production of conventional growth factors such as platelet-derived growth factor (PDGF). Interestingly, NGF has been found in significant concentrations in inflamed tissues’“, and itself induces production of IL-i in neuronai-like cell lines”. The role of NGF in regulating the innervation of embryonic tissue is well described (see Ref. 12), and investigation of this function has resulted in the discovery of several additional members of the neurotrophin family [brain-derived neurotrophic factor (BDNF) and neurotrophins NT-3, 84

TfNSVol. IR. No. 2. 1995

NT-S and NT-61. These fnctors are also expressed in mature tissues where, together with other cytokines, they might play important roles in growth and repair of damaged nerves (see Ref. 13). Amongst other important ‘neurotrophic’ factors that are present in peripheral nerve tissue is ciliary neurotrophic factor (CNTF), the principle cellular source of which is Schwann cells. In response to nerve injury, CNTF is transported axonally at an increased rate to the neuronal cell body14. Fibroblast growth factor (FGF) is also present in substantial amounts in nerve tissue, is synthesized by retinal ceils’s, and can be transported anterogradely by retinal ganglion neurones 16. Classical growth factors that are likely to be important in response to nerve injury, such as PDGF and TGF-p, are produced by both neurones and Schwann cells, as well as by inflammatory cells”~‘“. Except for the cytokines that are associated with growth and repair (neurotrophins, neuropoietins and other growth factors), few have been localized to peripheral neurones. It has been suggested that the ability of nerves to release mediators rapidly could provide an immediate source of cytokines”. However, apart from the chemokines, most effects of cytokines are induced slowly, relative to effects of neurotransmitters, since they act predominantly via modulation of gene transcription. The potential value of a rapid neuronai release of cytokines is therefore unclear, and its occurrence has not been demonstrated clearly. In the rht, interferon y (IFN-y)like immunoreactivity has been demonstrated in sensory and adrenal neurones and axotomized motor neurones?‘, however, the functional significance of this is obscure. lnterleukin lcu (IL-la) has been localized immunohistochemically to peripheral neurones with a similar distribution pattern to that of noradrenergic fibres”,“, and can be induced in PC12 cells by NGF (Ref. 11). This is interesting in NT-4,

im i

illlllll

view of the fact that IL-113 is the predominant form secreted by inflammatory cells although, like chrrF and FGF, both a and 13 forms lack the classical peptide signal sequence, which is considered necessary for protein secretion, and are probably released following cell disruption.

R~Ew

S. H o p k i n s a n d N , R o t h w e l l - Cytoldnes and the nervous system I ill.

B?

Periphery

CNS

Infection or inflammation -

~ IL-11~

l:ytokines as mediators between peripheral tissues and the CNS An important and largely unresolved question is whether cytokines released peripherally gain access to the CNS at effective concentrations. Cytokines, such as IL-I, IL-6 and TNF.a, have been proposed as signals that activate centrally controlled responses (for examp!,:, fever, sickness behavtour and neuroendocrine changes) to systemic injury and infection, but the means by which they communicate with the brain is still uncertain. The size and structure of cytokines is such that passive diffusion across the blood-brain barrier (BBB) is likely to be minimal, although actions at brain sites which lack a functional BBB, such as the organum vasculosum of the laminae termlnalis, are likely=. An active transport system for IL-1 and TNF.a from the blood to the brain has been described, which might be an important route of entry into the brain when plasma concentrations of cytokine are very high 23,24. However, as assays have become more discriminating, it has become clear that little or no bioactive or bioavailable IL-1 or TNF-a circulates, except after the most severe trauma. Given the very low rates of transport described (<0.1% of systemically injected IL-1 is found in brain), it seems unlikely that this is a physiologically significant mechanism. Furthermore, functional studies on fever and cardiovascular responses to systemic insults indicate that circulating IL-1 does not act directly on the brain or mediate endoto~Aninduced fever in the rat 2s.26. In contrast, circulating concentrations of IL-6 increase by several orders of magnitude during the development of fever 27, and this cytokine is transported into brain at a rate similar to that of IL-1 (Ref. 28). Thus, IL-6 is now a stronger candidate for the circulating endogenous p.vrogen and mediator of other systemic acute-phase host responses. Peripherally induced production of cytokines such as IL-1 and TNF-a might influence the brain indirectly as they are potent inducers of production of IL-6 in a variety of tissues (Fig. 1). The extent to which cytokines released peripherally promote production of cytokines within the brain is not known, though it seems possible that cytokines could influence the CNS via neural pathways. For example, vagotomy has been reported to inhibit hehavioural responses to systemic administration of endotoxin in the rat (R. Dantzer, pets. commun.), and C.fibre deafferentation inhibits febrile responses to hind-limb inflammation 29. Whatever the signalling mechanisms are between the periphery and the CNS, the relationship between central and peripheral production of cytokines is, to some extent, reciprocal, since centrally administered IL-1 increases peripheral synthesis of IL-6, apparently via opioid-receptor-mediated pathways 3°'31.

Cytokine expression in the CNS Despite the con~oversy surrounding the entry of

cytokines into the brain, measurement of cytokine

Inflammatory cells

/',,,

\

II.-1

TNF

ILl-R[

TNF-R

IL-6

Tissue cells

11.-6 - -

IL1-Rn?

I

?

......

--~ Fever thermogen~is

Fig. 1. PN$ and CN$ cytokines as mediators of hypothalamic activation. Tissue cytakines such as intedeukin 1 ilL-l) and turnout necrosis factor (TAll:) induce high levels of IL-6 secretion in tissues. Notable amounts of IL-6 enter the circulation and might cross the blood-brain barrier to the CNS. Additionally, synthesis of IL-113 is induced within the CNS, and might oct via type II.like receptors (ILl.R,?). Abbreviations: ILl-R, IL.1 receptoc and TNF-R, TNF receptor. protein and mRNA expression, and studies on isolated-cell systems, have confirmed that many cytokines are expressed within the brain or cells isolated from the CNS (see Table 2). Induction of IL-1 and IL-6 occurs in the brain following systemic administration of lipopolysaccharide33,49.s° (LPS) and, thus, might be relevant to the role of IL-I in the control of the hypothalamic responses described above. Contamination of brain tissue with !eukocytes, entry of fragments of LPS to the CNS, or induction of production of cytokines in brain endothelium cannot be excluded at this stage, and it will be of interest to see if this induction can he demonstrated using non-circulating exogenous stimuli. The site of synthesis of cytokines within the brain is dependent largely on the nature of the stimulus, so that although systemic disease seems predominantly to influence expression in the hypothalamus, brain damage causes local increases in synthesis. Immune cells, such as macrophages, T cells and neutrophils, which can invade the brain after injury or inflammation, are a rich source of cytokines. However, unlike peripheral tissues, entry of myelomonocytic cells into the bmln can be delayed until several hours after injury, and neutrophils rarely invade sl. Thus, early expression of ~v~.

t~.~. 2. i~.~

85

release of further mediators, such as prostaglandins. Receptors for Cell sources Rek Cytokines produced IL-l, IL-Z, IL-3, IL-6, TNF-a, and Stimulus for many growth factors, have Neuron& microgfia 32 33 Peripheralinfection. IL-lb. IL-6 been identified in brain tissue, endotoxin using radioligand-binding studies, Micro@, astrocpzs 34-36 IL-IO, IL-6. TNF-a. TGF-(3.IFN-T immunocytochemistry, or expresCNS infection,for MIP-I , MIP-2 example,malaria. sion of receptor mRNA. However, HIV, meningitis in most cases, the precise cellular cytomegalovirus location has not been elucidated. Micrqlii (new-ones?) The distribution of these receptors 374 IL-I B. IL-2 11-6,TNFa, Brain injury IL-S. UF. NGF. FGF. PDGF. usually corresponds to known EGF.TGF-B actions of cytokines in the brain, with highest densities fer most Neurones? 41.42 IL-I B. lL.6, TNFu. UF Convulsants cytoklnes in the hypothalamus Micrcglff. neurones, 41-45 IL-I B. 11.6, FGF. TGF-(3 lschaemia and hippocampus. An import-ant perivascularcells exception to this is IL-l. Although 35.44.46 Multiplesclerosis IL-I (3.IL.2 lL-6. Gfia. fjmphoqtes the classical type l receptor is TNFa, TNF-B. Iffrl-Y clearly present in the PNS, and has been cloned from rat Miii Down’s syndrome IL.18 47 sympathetic ganglia”, radioligandAlaheimer’sdisease IL.IB. !L-2 lL-6. (FGF?) Mfcroglffmacropllages? 47.48 binding studies and analysis of IL-l type I receptor mRNA expresAbbreviations EGF. epidemtal growrh kctc~ i=GF. fkoblast m factor IFN. inm+?mw II_ interkukin sion have generally failed to reveal UF. leukaemiainhii facmr. MIP. macqbage inflmmatmy prmtinz NGF. grmmhfacax PDGF, pktcktderived receptors in the hypothalamuss9@‘. growdl lictol However, a second receptor with unusual selectivity for IL-Q3 has been reported in the qtotines within the brain presumably indicates production by resident brain cells- Although there hypothalamus 61. Central injection of a monoclonal are probably multiple mechanisms of cyto-kine antibody, raised to the human type II IL1 receptor, inhibits the fever induced by peripheral endotoxin induction in the brain, it is hkely that cytokine and intracerebroventricular, but not peripherally, cascades exist, as are apnarent in the sequential injected IL-1 (Ref. 25) and, furthermore, the antiinduction of TNF-a, IL-I and IL-6 during infection of the CNS (Ref. 52). Several cytokines can regu- body binds to glial-like cells within the hypothalamus (G. Luheshi, S. Tou~mond, C. Davies and N. late their own synthesis, as well as the production of other cytokines (for example. IL-I, TNT-a and Rothwell. unpublished observations). This is of interest in view of the demonstration that the type II NGF). in peripheral The most abundant source of cytoklnes. particu- reqrtor is apparently non-functional larly after local damage, appears to be activated cellsa. and that the anti-type II receptor antibody, which inhibits the effects of IL-l, binds to the major microglia, although neurones, astroglia. pernascular and endothelial cells can also express cytokines. The histocompatibility complex (MIK) HLA-DR alpha expression of IL-l. IL-6 and l-N&a seems to be great- and beta chains”‘. Whether the currently characterest in the hypothalamus and hippocampus. with ized type II receptor, or a ditinct but related receplower amounts tn the cortex and brain-stem regions, tor subtype, is functional within the CNS is therefore au& detectable D~WIS in o;har brain re@onP”‘. As unclear. yet, few comparhons have been made between One of tire characteristic features of cytokine actrvitv that has confounded a simple understanding of thgt function is the extent to which they share activities- Members of some cytokine families, such as the neurotrophins and the chemokhres, do show distinct homologies, and there is some shared affinin- for receptors, but thii cannot explain fully this phenomenon. Although the intracellular signalling pathways resportsib!e for activation are not well defined for most cytokines, a partial explanation has emerged from molecular characterization of the receptor molecules (see Refs 64-67) which, unlike most cytoklnes, can be grouped into structurally related famiiii. Dre haemopo!etic cytolk%u+receptor superfamily bmding proteins or receptors for IL-3 to , gmnuloqte CSF fG-CSR, LIF and CNTF. Another member of this family is a 130 kDa glycoprotein (gpt30, or CDwl30) that associates with the binding proteins for IL-6 (IL6 receptor, or CXX?6k, IL-IS, LlF, oncostatin M (GM) and CNTF. tation of gpp1130 with these specific binding k-ins essentbally defines the newly described

TABLE 2. Cytokine synthesis in

the brain

R~VI--~

$, Hopklns and N. Rothwell - CFokines and ~henen~m sym~ I

neuropoietin family (see Table 1), although IL-11 is not yet included. In the case of CNTF, LIF and OM receptors, the LIF-receptor f3 chain (LIF-RI3) also forms part of the active receptor complex, together with gpl30 (see Refs 65 and 68-70). Both gpl30 and LIF-R[~ act as signal transducers. They activate tyrosine kinases within the cell, following receptor-complex formation induced by binding of cyto-kines. This common signalling mechanism partly explains why this family of cytokines shares so many activities, despite the specificity of the individual receptor complexes, both in neural and other tissues. Another interesting consequence of sharing gp130 arises from the fact that, in common with many other cytokine receptors, the extracellular portions of IL6 and CNTF receptors can be released as soluble, ligand-binding proteins. However, in contrast to other soluble cytokine receptors, the IL6 and CNTF receptors not only fail to neutralize their ligands, but potentiate activity via high-affinity binding to gpl30/LIF-R[3. Therefore, complexes of IL.6 or CNTF with their respective soluble receptors can potentially activate any cells with surface gpl30, or gpl30 plus LIF-R[3, respectively, regardless of whether they possess specific IL6 or CNTF receptors themselves. The high-affinity neurotrophin receptors are a family of homologous, homodimeric tyrosine kinases (Trk). Although each Trk exhibits preferential binding (NGF for TrkA, NT-4/S and BDNF for TrkB, and NT-3 for TrkC), there is evidence for some promiscuity. The receptors are distributed widely throughout the periphery and CNS, however, the CNS distribution of TrkA seems more restricted (for review, see Ref. 13). Recent observations of mice with nullmutations of each of these receptor types have provided evidence for an important role in the develop. ment of the PNS (see Ref. 67). The distinct p75 low affinity NGF receptor (pTSL~FR) is a mem-ber of a receptor family that includes the TNF re- ceptors (type I and IlL CD30, CD40 and the F a s antigen. Although the precise role of the p75 LN~R is unclear, since it binds each of the neuro-trophins with a lower affinity than the Trk recep-tors and has no apparent signalling function, it might regulate neurotrophin binding or transport in some way (see Ref. 51). Its importance is, however, demonstrated by the loss of sensory fibres that occurs in mice with a targeted mutation of the p75 L~GFRgene 7t. Regions of homology in ILl, IL6, PDGF, M-CSF, G-CSF and stem-cell factor receptors identify them as members of the immunoglobulin superfamily. However, the homology is restricted to extracellular regions, and ILl, !L6 and G-CSF have no identifiable intracellular signalling function, such as the tyrosine-kinase activity possessed by the other members of this cytokine-receptor family. Characterization of the chemokine receptors for IL-8, macrophage inflammatory protein (MIP-1) and melanoma growth stimulatory activity (MGSA)/GRO has shown them to be members of the receptor family con- taining seven hydrophobic membranespanning domains coupled to G proteins. The ensuing induction of Ca z÷ transients results in rapid activation of events such as chemotaxis or exocytosis, which distinguishes this family of mediators and receptors, since activation of most other

cytokine receptors results in induction of events that requires activation of genes.

Overview Studies on the localization and expression of cytokines in response to specific stimuli have important implications for the actions of cytoldnes in the nervous system. Many cytoklnes have now been identified in the PNS and CNS and their receptor mechanisms are being revealed gradually. In several cases, distribution of cytokines and their receptors correlates with known actions of exogenous cytokines. It is clear that cytokine expression Is upregulated rapidly in situations of tissue stress, and that cytokines have important actions that are consistent with a role in restoration of tissue homeostasis. However, it is still uncertain whether their expression is important in other physiological situ. ations subsequent to embryogenesls. Pmstaglandlns, like cytokines, have wlde ranging biological actions, and can be synthesized in most tissues, but Inhl. bition of their synthesis has remarkably few effects in the absence of inflammation. Studies of animals with inactivated cytokine genes further suggest that the functions of cytokines are rather more restricted than the reported pleiotropic effects suggest, although some caution must be exercised in interpreting data from animals in which a gene has been deleted throughout development. Amongst issues that have not been addressed adequately, and which are crucial to evaluating the importance of cytokine expression, are quantitative considerations. The concentrations of cytokines expressed, and available biologically, are not "known in most cases, making it very difficult to establish an accurate link between apparent expression and observed experimental effects of particular cytokines. Currently, relatively little information is available as to whether cytokine receptors in the nervous sybtem are the same as those identified in other tissues. Some studies, largely on IL-1, indicate that receptors in the nervous system might not be entirely homologous with those characterized in other tissues. Certainly, there is a strong precedent for varied peptide receptors in the CNS, the existence of which might allow selective pharmacological modification. Understanding the nature of cytokine.receptor subtypes, and their relation to signal-transduction mechanisms and function will be particularly important in view of the diversity of cytoldne action on the net~ous system and their suggested roles, which will be discussed in the second part of this review (see March issue). Selected references 1 Lotz, M., Vaughan, J.H. and Cm~n, D.A.11988)Sc/m~241. 1218-1221 2 Ansel,J.C. et u!. (leO3)J hnmlmol, i SO. 4 4 ~ 3 Sakagami, Y. et aL (1993) 1. Bone Miner. Res. 8. 811-R16 4Nakamura, A., Kohsaka, T. and Johns, F.J. eY;t93~ I. Hypertens. 11,491-497 S V a n Gool, J. et aL 11990) Clin.Immunol. l ~ l w l . $7. 200-210 6 Morrow, L.E. et aL (1993) Am. 1. Phi.~oL 264. RIOIO-RI016 7 Shadiack, A.M. et al. (1993) L Neuro.~. 13, 2601-2609 8 Lindholm, D. et al. (1987) Nature 330. 658-6.59 9 Hattori, A. et al. (1993) 1. Biol. Clam. 268, 25~'7-2582 10 Aloe, L. et aL (1992) Ar/hrf6s Rbeton. 3S, 351-355 11 Alheim, K. et al. (1991) 1 ~ . Nail Acad. 5t~. USA88. 9302-93~'~ vol.t~ ~

Z l~s

87

REVIEW

S.Hopklnn and N. Rothwell-

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Cfloklnerand the nervous system I

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40 Logan, A. and Berry, M. (1993) Trends Pbnrtnncol. Sri. 14, 337-343 41 Minami, M. et al. (1990) Bloc/tern. Biopltys. Res. Comtntm. 171, 832-837 42 Mlnaml, M. et al. (1991) Nerrroscietm Lett. 123, 254-256 43 Mlnaml, M. et al. (1992) I. Neifrochetn. 58,390-392 44 Rengzon,J. et al. (1991) Sot. Neurosci. Abstr. 17,183 45 Flnklesteln, S.P. et al. (1990) Stroke 21, 122124 46 Merrill, J.E. et al. (1992) Proc. Nd Ad. Sci. USA 89,574478 47 Griffin, N.S.T. et al. (1989) hoc. Nd Acnd. Sri. USA 86, 761 l-7622 48 Strauss,S. ct al. (1992) Lab. hvest. 66, 223-230 49 Muramami, N. et al. (1993) E~zriorrir~ology133, 25742578 SO Gattl, S. and Bartfai, T. (1993) Ernin Res. 624, 291-294 51 Ferry, V.H., Andersson,P-B. and Gordon, S. (1993) Trends Neurosci. 16,268-273 52 Waagc, A. etal. (19R9) \. Exp. Med. 170, 1859-1867 53 Dreder, CD., Dinarello, C.A. and Saper, C.B. (1988) Science 240,321-324 $4 Schobitz, IL et al. (1993) Eur. 1. Netfrosci. 5, 1426-1435 55 Romcro, L.I. et al. (1993) Nertroettllocritrolo~ 57,892-897 56 Fontana, A. et al. (1993) In Clinical Applicntiotts ofcytokines: RoleItt Pntlto,qctte.sls,Dlngttosis, totri Tlrerapy (Oppcnhclm, J.J., Rosslo, J.L. and Gearing, A.J.H., cds), pp. 357366, Oxford Unlverslty Press 57 Patterson, P.H. and Nawa, H. (1993) Cell 72, 123-137 SR Hart, R.P. et al. (1993) I. Ne~rrobnt~r~a~ol. 44, 49-56 59 Haour, F.G. et al. (1990) Pros. Nettraetrclocrltzitnmttttol. 3, 194-204 60 Duncan, E.T. and De Sousa, E.B. (1993) II~I~I~IIO/. To&y 14, 171-176 61 Katsuura, G., Gottschall, P.E. and Arlmura, A. (1988) Ulocltettt. Bloplrys. Res. Cotr~ttt~~tt. 156, 61-67 62 Sims, J.E. cI RI. (1993) Proc. NatI Acnd. Sri. USA 90, 61.%-6159 63 Gayle, M.A. et al. (1994) Cytokirie 6,83-86 64 dall, A.K. and Rao, M.S. (1992) Trends Nerrrosci. lS,35-37 65 Taga, T. and Kishlmoto, T. (1992) FASEB/. 6,3387-3396 66 Chao, M.V. (1992) Nerwt~ 9, 583-593 67 Davles, A.M. (1994) Nnhrre 368, 193-194 68 Gearing, D.P. et al. (1992) S&m= 255, 1434-1437 69 Davis, S. and Yancopoulos, G.D. (1993) Qtrr. Opitt. Newobiol. ?.2Al-2% _, -.._ -..70 Yin, T. et al. (1993) /. Ltttnrttrol. 151, 2555-2561 71 Lee, K-F. et al. (1992) Cell 69, 737-749

You say CQC2 and I say Cdc2p They say cdc-2 and we say cdc2 Italic? Roman? yphens? Superscripts? Confused about genetic nomenclature? You’re not alone: with the ever expanding amount of information on genes, proteins, mutants and strains, and the increasing importance data from many genetic systems, it becomes more and more difficult to get it right.

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