Review

Mediators of , 5, 417-423 (1996)

CYTOKINES and their receptors are involved in the as cellular pathophysiology of many diseases. Here we pre- sent a detailed review on cytokines, receptors and communicators signalling routes, and show that one important lesson from biology is the complex and diverse regulation of cytokine activity. The activ- cA ity of cytokines is controlled at the level of trans- R. Debets and H. F. J. Savelkoul cription, translation, storage, processing, post- translational modification, trapping, binding by soluble proteins, and number and/or Department of Immunology, Erasmus University, function. Translation of this diverse regulation in P.O. Box 1738, 3000 DR Rotterdam, The Netherlands strategies aimed at the control of cytokine activity will result in the development of more specific and selective drugs to treat diseases. CACorresponding Author Key words: Control of activity, Cytokine, Interference in cytokine activity, Receptor, Signalling routes

Introduction lation and act locally to restore homeostasis. Cytokines bind with high affinity to specific For over two decades, it has been recognized receptors on the surface of target cells. When that immune-competent cells produce peptide cytokine receptors are expressed on the cyto- mediators, now termed cytokines. Cytokines act kine-producing cell, autocrine cellular activation as chemical communicators between cells, but may be the result. If the receptor is expressed mostly not as effector molecules in their own on a neighbouring cell, binding may result in right. The biological function of many cytokines paracrine cytokine activation. These features is mediated through their ability to regulate could explain the sometimes high local concen- gene expression in target cells. Recent develop- tration and profound local effects of cytokines. ments have made it clear that cytokines play A characteristic feature of cytokines is their crucial roles in the regulation of normal growth functional pleiotropy (cytokines result in di- and development, protection against inflamma- verse effects upon binding to different target tion and infection, neoplastic transformation, cells) and redundancy (several cytokines can wound-healing and angiogenesis. For example, take over each other's effects), which can be inflammatory mediators are involved in the largely explained at the molecular level of pathophysiology of septic shock and they are receptor systems (see below). often associated with disease severity. In such diseases the balance between pro-inflammatory Families of Cytokines cytokines (interleukin-1 (IL-1), IL-6, IL-8, tumour necrosis factor-alpha (TNF

Table 1. Structural families of cytokines and their receptors Families of cytokines Members Superfamilies (SF) of cytokine receptors Haemopoietins SF class IL-6, IL-11, LIF, OM, CNTF, CT-1 gp130 IL-3, IL-5, GM-CSF common 13-chain IL-2, IL-4, IL-7, IL-9, IL-13, IL-15 common y-chain IL-10, IFN-, IFN-I, IFN-y Cytokine receptor SF class II M-CSF Immunoglobulin SF IL-1 IL-lcz, IL-113, IL-lra, FGF-(z, FGF-I Immunoglobulin SF TNF TNF-ot, TNF-I, LT-I TNF receptor SF TGF-z TGF-(z, EGF Protein tyrosine kinase receptor SF TGF-13 TGF-II, TGF-132, TGF-I3 TGF-13 receptors PDGF, VEGF Immunoglobulin SF NGF TNF receptor SF Chemokines SF subfamily IL-8, GRO-(z, GRO-I, GRO-y, ENA-78, IP-10, MIG, GCP-2, PBP (and its cleavage products: CTAP-III, thromboglobulin, NAP-2), PF-4, SDF-I(z, SDF-113 subfamily MCP-1, MCP-2, MCP-3, RANTES, 1-309, MIP-I, MIP-113 aThe families of cytokines are named after a representative member (except for the haemopoietins and chemokines). bThe family of haemopoietins also comprise G-CSF and (Epo), but data on their receptors are insufficient for receptor classification. CTo date, the TGF-I receptors are not grouped into a SF of cytokine receptors. dAbbreviations (apart from those explained in the text): CTAP, connective tissue activating protein; ENA, epithelial-derived neutrophil attractant; GCP, granulocyte chemotactic protein; IP, IFN-T-inducible protein; LT, ; MIG, manokine induced by IFN-y: MIP, macrophage inflammatory protein" NAP, neutrophil-activating peptide; PBP, platelet basic protein; PF, platelet factor; RANTES, regulated on activation, normal T-cell expressed and secreted; SDF, stromal cell-derived factor. growth factor (PDGF), vascular endothelial superfamily (e.g. IL-6 receptor belongs to both growth factor (VEGF) and the class I receptor and immunoglobulin super- (NGF) (cysteine knots); and chemotactic cyto- families). All cytokine receptors are single kines (chemokines) (triple-stranded, anti-parallel transmembrane proteins, except for the chemo- ]3-sheets in Greek key motiO.2-4 The large family kine receptors which contain seven transmem- of chemokines can be subdivided into at least c- brane domains. chemokines (the two most amino-proximal The cytokine receptor superfamily class I cysteine residues are separated by an interven- receptors are characterized by the presence of ing amino acid: CXC) and [3-chemokines (CC), combinations of cytokine and fibronectin III which are functionally distinct, as they predomi- domains in the extracellular regions. The amino nantly attract neutrophils and monocytes, terminal cytokine domain(s) contains four con- respectively. 5 It is intriguing that different struc- served cysteine residues, and (one of) the tural domains of cytokines (e.g. IL-I[3) may membrane proximal fibronectin III domains display different or even antagonistic cytokine contains the Trp-Ser-X-Trp-Ser (WSXWS) motif activities.6 required for binding.7 Functional class I receptors consist of a complex of two or three Families of Cytokine Receptors receptor chains. These multisubunit receptors can be grouped according to the identity of Cytokine receptors are classified into several common chains which are required for high superfamilies based on common homology re- affinity ligand binding and . gions. The main superfamilies recognized today Three subgroups of class I receptors were are the cytokine receptor superfamilies class I identified sharing either gpl30 (a glycoprotein and class II, the immunoglobulin superfamily, with a relative molecular mass (Mr) of 130 kDa, the TNF receptor superfamily, the protein ty- cluster of differentiation (CD) 130), the com- rosine kinase receptor superfamily, and the mon -chain (Mr: 120 kDa, KH97) or the com- chemokine receptor superfamily. Figure 1 illus- mon ,-chain (Mr: 64-kDa) (see Table 1 and Fig. trates schematically these cytokine receptor 1). The gp130 chain is shared by the receptors. superfamilies. It should be noted that the super- for IL-6, IL-11, ciliary neurotrophic factor families are not restricted to cytokine receptors (CNTF), leukaemia inhibitory factor (LIF), on- (for example, several hormone receptors and costatin M (OM) and cardiotrophin-1 (CT-1).9 leukocyte membrane polypeptides also belong Ligand binding by this group of receptors to cytokine receptor superfamilies) and several induces homodimerization of gpl30 (in case of cytokine receptors belong to more than one IL-6R and IL-11R) or heterodimerization of

418 Mediators of Inflammation Vol 5 1996 Cytokines as communicators

Cytokine receptor SF class

common

Cytokine receptor SF class Immunoglobulin SF TNF receptor SF ,.),JN F (homotrimer)

Chemokine receptor SF

-eprobtnn-bund.

FIG. 1. Superfamilies of cytokine receptors. Examples are depicted, containing a representative cytokine bound to its receptor. Note that signalling through the IL-6 receptor complex is preceded by gp130 homodimerization, and that IL-1 receptor signalling is characterized by a cascade of protein phosphorylation. For simplicity reasons, the protein tyrosine kinase receptor SF is not shown, as it only covers the interaction with the growth factors TGF-c and EGF. Abbreviations are explained in the text and Table 1. gp130 and LIFR (in case of CNTFR). LIE OM los and c-jun induction).'101 The signalling and CT-1 are believed to directly induce hetero- routes which result from activation of the dimerization of gpl30 and LIFR (OM and common chains are discussed below. perhaps CT-1 also induce heterodimerization of The cytokine receptor superfamily class II gpl30 and the ligand-specific receptor). The receptors ( (IFN) R and IL-IOR) con- LIFR, granulocyte-colony stimulating factor (G- tain one or two extracellular fibronectin III CSF) R and IL-12R are highly homologous with domains, which lack the WSXWS motif charac- gpl30 and belong to the so-called gp130 family. teristic of the class I receptors7 Ligand binding The common -chain is shared by IL-3R, IL-5R may induce receptor homodimerization (e.g. and granulocyte and macrophage-CSF (GM-CSF) IFN-yR) and activate the Janus kinases OAK)- R, whereas the common y-chain is shared by IL- signal transducers and activators of transcrip- 2R, IL-4R, IL-7R, IL-9R, IL-13R and IL-15R. tion (STAT) pathway (see below). The immuno- Recent evidence suggests that the cytoplasmic globulin superfamily receptors (IL-1R, IL-6R, parts of these signal transducing chains harbour FGFR, M-CSFR, PDGFR, VEGFR, two functional domains: a membrane-proximal R (SCFR)) contain one or more domains with region which is essential for proliferation signals the characteristic immunoglobulin fold.12 Recep- (c-myc induction), and a membrane-distal region tors belonging to the protein tyrosine kinase which is essential for differentiation signals (c- receptor superfamily (EGFR, insulin-like growth

Mediators of Inflammation Vol 5 1996 419 R. Debets and H. E J. Savelkoul factor (IGF) R, FGFR, M-CSFR, PDGFR, VEGFR, Table2. Selective usage of JAK kinases and STAT factors SCFR) are in general growth factor receptors by cytokine receptors with an intracellular tyrosine kinase catalytic Receptor JAKkinases STATfactors domain.13 Ligand binding by these receptors IL-2 1,3 3,5 induces receptor homo- or oligomerization, IL-3 1,2 5 autophosphorylation and subsequent signalling. L-4 1,3 6 Members of the TNF receptor superfamily L-5 1,2 5 L-6 1, 2, Tyk2 1,3 (TNFR and NGFR) are characterized by three or L-7 1,3 5 four cysteine-rich repeats in the extracellular L-9 1,3 3 part of the molecule.14 These receptors may L-10 1, Tyk2 1,3 L-11 1, 2, Tyk2 not known bind more than one ligand. Little is known L-12 2, Tyk2 3,4 about the mode of signal transduction by L-13 not known 6 receptors of this superfamily. Receptors of the L-15 1,3 5 FN-c/I 1, Tyk2 1,2,3 chemokine receptor superfamily are coupled to FNq, 1,2 guanosine triphosphate (GTP) binding proteins G-CSF 2 not known which, after ligand binding, activate lipases, GM-CSF 1,2 5 5 CNTF 1, 2, Tyk2 3 kinases, phosphatases and ion channels OM 1, 2, Tyk2 3 LIF 1, 2, Tyk2 3

aModified from Refs 16, 17 and Schreiber RD, oral presentation, Cytokine Receptor Signalling cytokine meeting, 6-10 October 1996, Geneva, Switzerland. Recent studies have demonstrated that the cytoplasmic domains of cytokine receptors are cytokine genes distinct combinations of these critical for signal transduction. Ligand-induced transcription factors determine the transcrip- receptor di-or oligomerization typically results tional activity of these loci. Activation of the in activation of (receptor-associated) protein individual cytokine genes requires binding of tyrosine kinases (such as members of the SRC distinct sets of transcription factors. The data kinases OAK)) which are associated with the on the involvement of the JAK/STAT pathway cytoplasmic tails of cytokine receptors. Subse- do not preclude that the activation of these quently, activated JAK1 are thought to phos- genes may be secondary to the activation of the phorylate several substrates (such as the above mentioned combination of transcription receptors themselves, members of the RAS- factors. mitogen activated protein (MAP) kinase cas- cades, and transcription factors). Phosphoryla- tion of tyrosine-based motifs in the cytoplasmic Soluble Cytokine Receptors domains of the receptors is followed by specific docking and activation of members of the STAT It seems that essentially all single transmem- family of proteins.15'16 Activated STATs form brane cytokine receptors exist as soluble homodimers, translocate into the nucleus, and forms.19 Soluble receptors can be translated bind to specific responsive elements to initiate from differentially spliced pre-mRNA molecules gene transcription. This JAK-STAT pathway re- lacking the transmembrane domain (e.g. IL-4R, suits in rapid and specific transcriptional IL-5R, IL-6R, IL-7R, IL-9R, GM-CSFR, G-CSFR, activation of target genes, and may, at least in TGF-cR). However, the presence of mRNA for part, contribute to cytokine-specific responses soluble receptors not always seems to represent through selective activation of individual JAK protein synthesis. Soluble receptors can also be kinases (JAK1, JAK2, JAK3 and TYK2)and STAT generated by of cell surface recep- factors (STAT1 through STAT6).7'18 Table 2 tors (e.g. IL-1R, IL-2Rcz, IL-6R, gpl30, PDGFR, presents more details on receptor-mediated NGFR, TNFR, TGF-R) and by phospholipase activation of induced JAK kinases and STAT action on the glycosyl-phosphatidylinositol factors for various cytokine receptors. Besides (GPI) anchor of CNTFR. Proteolytic shedding this tyrosine kinase pathway, also the serine may be controlled by protein kinase C and may kinase pathway is involved in cytokine-receptor involve a metalloprotease, since phorbol myris- mediated signalling. In activated T-cells the tate acetate (PMA)-induced shedding of IL-6R, activation of transcription factors, like activating TNFR type I and II as well as membrane TNF-(z protein-1 (AP-1) (fos/jun dimers), members of is blocked by a metalloprotease inhibitor, which the nuclear factor in activated T cells (NF-AT) was first identified as TNF-0t protease inhibitor family and NF-KB, play distinct roles in the (TAPI).2'2] Soluble cytokine receptors are found induced differentiation. In the promotors of in appreciable amounts in body fluids, although

420 Mediators of Inflammation Vol 5 1996 Cytokines as communicators the exact cellular source and function of these cellular viral proteins have been described that proteins is not completely clear. interfere with cytokine maturation and cyto- kine-mediated responses.22 Virokines Cytokine Biology The immunological relevance of cytokines and (soluble) cytokine receptors is clearly illustrated The current view on cytokine biology is that of by the observation that several pathogenic virus a network of cytokines with additive, synergistic strains, particularly pox viruses, encode pro- and opposite effects, and inducers and inhibi- teins which counteract the anti-viral cytokine tors of the expression of cytokines and/or their activity during the host response.22 Examples of receptors, which combine to give an overall these so-called virokines include a homologue biological (or clinical) response.26 Cytokines are of the host suppressive cytokine IL-10 encoded potent molecules, of which the activity is by Epstein-Barr virus2 and several poxviral regulated at multiple levels. homologues of soluble IL-1R (sIL-1R), sTNFR First, stimuli are required to induce as well as and sIFNR, which prevent interaction of the to suppress the transcription of most cytokine ligands with cellular receptors.2z'z4 In addition, genes. For example, infectious or toxic agents, herpes viruses and cytomegalovirus encode mechanical injury, inflammatory mediators, and chemokine receptors which are expressed on cytokines themselves (e.g. IL-1, TNE IFN-y) are the membrane of infected cells, but probably potent cytokine inducers, whereas glucocorti- display an altered function.2 Furthermore, intra- coids, prostaglandins and cytokines (e.g. IL-10

functionally active cytokine

ICE inhibitors anti-cytokine (auto)antibodies soluble cytokine receptors natural or pharmacological antagonists processing tokine receptor

hibit variant _eln CSAIDs transnA ucleot.de ranso rl ptlo,A rai oSz/rSeesn inCiindeSs

FIG. 2. Schematic outline of a target cell (represented only by a plasma and a nuclear membrane) illustrating the synthesis and activation of cytokines and cytokine receptors. At multiple sites interference can potentially lead to inhibition of production and/or activation of cytokines and their receptors. Numerous drugs have been reported which interfere with cytokine, receptor synthesis or activation. Those mentioned in the figure, therefore, merely serve as an example. Abbreviations (apart from those explained in the text): CSAID, cytokine synthesis anti-inflammatory drug; ICE, interleukin-ll converting enzyme.

Mediators of Inflammation Vol 5 1996 421 R. Debets and H. E J. Savelkoul and TGF-[3) are potent inhibitors of cytokine signalling pathway' is the fact that gp130 is gene expression. Note that genetic polymorph- present essentially on all cell types, whereas IL- isms (e.g. IL-lc, IL-lra and TNF-27-29) may 6R and CNTFR are not expressed ubiquitously. contribute to interindividual differences in cyto- On the other hand, soluble proteins may kine expression upon stimulation. antagonize cytokine activity by acting as scaven- Second, the extent of cytokine protein pro- gers of cytokines (by competing with mem- duction is limited, since the consensus se- brane receptors), by neutralizing their activity, quence UUAUUUAU in the 3' end of most by enhancing antibody-dependent cell-mediated cytokine mRNAs promotes message instability.5 cytotoxicity, by preventing extravascular escape Translation of cytokine mRNA transcripts may, and by promoting excretion.4 Whether soluble in addition to the first signal, require an proteins will act as agonists or antagonists of additional signal (e.g. in the case of IL-I).31 cytokine activity is, at least in part, determined Third, several cytokines are not released by the ratio between membrane receptors and through the classic secretory pathway. These soluble proteins: the predominance of mem- cytokines are produced as larger biologically brane receptors favours agonistic activity, inactive precursor molecules, which are stored whereas the predominance of soluble proteins within the cytoplasm (e.g. IL-1, IL-8, GM-CSF, favours antagonistic activity.44 TGF-[3, PDGF) or expressed on the plasma Finally, cytokine activity can be regulated by membrane (e.g. TGF-c, IL-lc, TNF-cO, and need modulating the number and/or function of to be proteolytically cleaved to release the membrane receptors. Receptor number may be mature molecule (e.g. TGF-{x, IL-Iz, IL-I, TNF- modulated by controlling gene expression, in- cz).2-4 Extracellular enzymes may also contri- ternalization or the generation of soluble recep- bute to the processing of precursor molecules tors. Receptor affinity and/or function may be (e.g. IL-I, TGF-).5,6 modulated by affecting receptor phosphoryla- Fourth, post-translational modifications (e.g. tion and/or glycosylation, by competition for cleavage-site of leader peptide, glycosylation, common receptor chains or signal transduction phosphorylation and/or multimerization) affect molecules16'41 or by binding cytokine receptor the biological activity of mature cytokines (e.g. antagonists. These latter molecules bind to the It-6, It-8).37-39 receptor but do not cause signal transduction Fifth, once secreted, several cytokines are (for example, IL-lra, IL-462 and (p40)2 antag- trapped by cell surface binding proteins (e.g. onize IL-1, IL-4 and IL-12 functions, respec- TGF-), extracellular matrix (e.g. LIE IL-1, FGF), tively).45-47 stromal cells (e.g. IL-3, IL-5, GM-CSF) and Strategies aiming at controlling cytokine activ- endothelial cells (e.g. IL-8).3'4 It should be ity take this into account and are schematically noted that the intracellular, membrane and illustrated in Fig. 2. extracellular pools of cytokines are available for rapid maturation and/or release in response to stimulation. References Sixth, soluble proteins which bind to cyto- 1. Kornelisse RE Hazelzet JA, Savelkoul HFJ, Hop WCJ, Suur MH, kines can potentiate or antagonize cytokine Borsboom ANJ, Risseeuw-Appel IM, Van Der Voort E, De Groot R. The activity. The proteins bind to cytokines either relationship between plasminogen activator inhibitor-1 and proinflam- 41 matory mediators in children with meningococcal septic shock. nonspecifically such as 2-macroglobulin or J lnfect Dis 1996; 173:1148-1156. specifically such as autoantibodies to cytokines 2. Boulay JL, Paul WE. The interleukin-4 family of . Curr Opin Immunol 1993; 3: 573-581. (e.g. IL-I, IL-6, IL-8, IL-IO, monocyte chemo- 3. Callard R, Gearing A. The Cytohine Factsboole. London: Academic tactic protein-1 (MCP-1), IFN-x)42,4 and soluble Press, 1994; 12-27. 19 4. Debets R, Savelkoul HFJ. Cytokine antagonists and their potential cytokine receptors. So far all known soluble therapeutic use. Immunol Today 1993; 15: 455-458. forms of cytokine receptors were found to 5. Baggiolini M, Dewald B, Moser B. IL-8 and related chemotactic cytokines-CXC and CC chemokines. Adv Immunol 1993; 55: 97-179. retain their ligand binding capacity. On the one 6. Boraschi D, Nencioni L, Villa L, Censini S, Bossf P, Ghiara P, Presentini hand, these soluble proteins may agonize cyto- R, Perin E Frasca D, Doria G, Forini G, Musso T, Giovarelli M, Ghezzi P, Bortini F, Besedovsky HO, Del Rey A, Sipe JO, Antoni G, Silvesta S, kine activity by acting as chaperons, increasing Tagliabue A. In vivo stimulation and restoration of the immune the cytokine's persistence.'4,44 Moreover, in case response by the non-inflammatory fragment 163-171 of human inter- leukin 1. J Exp Med 1988; 168: 675-686. of slL-6R and sCNTFR, the soluble proteins form 7. Bazan JE Structural design and molecular evolution of a cytokine a biologically active binary complex with their receptor superfamily. Proc Natl Acad Sci USA 1990; 87: 6934-6938. 8. Kishimoto T, Taga T, Akira S. Cytokine signal transduction. Cell 1994; ligands (IL-6msIL-6R, CNTFmsCNTFR) which "76: 253-262. may act on cells only expressing on their 9. Kishimoto T, Akira S, Narazaki M, Taga T. Interleukin-6 family of gp 130 cytokines and gpl30. Blood 1995; 86: 1243-1254. cell surface, but not IL-6R or CNTFR (normally 10. Murakami M, Narazaki M, Hibi M, Yawata H, Yasukawa K, Hamaguchi anticipated as cells being unresponsive to IL-6 M, Taga T, Kishimoto T. Critical cytoplasmic region of the IL-6 signal 19 transducer, gpl30, is conserved in the cytokine receptor family. Proc or CNTF). Note that in line with this 'trans- NatlAcadSci USA 1991; 88: 11349-11353.

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