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47 CC chemokines Alberto M a n t o v a n i ~,e, M a s s i m o LocatF a n d Silvano So;~zani 1,3 ~Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy 2University of Milan, Milan, Italy 3University of Brescia, Brescia, Italy To travel is to take a j o u r n e y into yourself. D e n a Kaye

INTRODUCTION CC chemokines are the most numerous and diversified family of the four subgroups defined, based on the Cys motif (CC, CXC, C, CX3C). In humans, it includes at least 25 members interacting with at least 11 signaling receptors (Rollins, 1997; Mantovani, 1999; Zlotnik and Yoshie, 2000). CC chemokines have been discovered following different pathways, ranging from biological and biochemical identification to direct cDNA cloning to, more recently, in silico cloning by gene bank mining. For instance, in the case of CCL2 (monocyte chemotactic protein 1, MCP-1), it had already been noted in the early 1970s that supernatants of activated blood mononuclear cells contained attractants active on monocytes and neutrophils. Subsequently, a chemotactic factor active on monocytes was identified in culture supernatants of mouse (Meltzer et al., 1977) and h u m a n (Bottazzi et al., 1983) tumor lines and was called tumor-derived chemotactic factor (TDCF) (Bottazzi et

The Cytokine Handbook, 4th Edition, edited by Angus W. Thomson & Michael T. Lotze ISBN 0-12-689663-1, London

al., 1983; 1985). TDCF was at the time unique in that it was active on monocytes but not on neutrophils (Bottazzi et al., 1983) and had a low (12 kDa) molecular weight (Bottazzi et al., 1983). Moreover, correlative evidence suggested its involvement in the regulation of macrophage infiltration in murine and h u m a n tumors (Bottazzi et al., 1983; Mantovani et al., 1992). A molecule with similar cellular specificity and physicochemical properties was independently identified in the culture supernatant of smooth muscle cells (SMDCF) (Valente et al., 1984). The JE gene has been identified as an immediate-early PDGF-inducible gene in fibroblasts (Zullo et al., 1985; Rollins et al., 1988). Thus, in the mid-1980s a gene (JE) was in search for function and a monocyte-specific attractant was waiting for molecular definition. In 1989, MCP- 1 was successfully purified from supernatants of a h u m a n glioma (Yoshimura et al., 1989a), a h u m a n monocytic leukemia (Matsushima et al., 1989) and a h u m a n sarcoma (Graves et al., 1989; Van Damme et al., 1989; Zachariae et al., 1990): sequencing and

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molecular cloning revealed its relationship with the long-known JE gene (Furutani et al., 1989; u et al., 1989b; Bottazzi et al., 1990). CC chemokines act on a most diverse spectrum of target cells, mostly but not exclusively in the hematopoietic system. Non-hematopoietic elements, including epithelial cells, fibroblasts and vascular elements have been shown to express receptors for and respond to CC chemokines, although the actual in uiuo importance of these responses remains to be defined. The action of CC chemokines is regulated at the level of agonist production and processing as well as at the level of receptor expression and coupling. Therefore an analysis of ligands must necessarily consider receptors. In this chapter we will summarize the general features of CC chemokines and their receptors. Certains aspects of the pathophysiology of CC chemokines will be discussed. In particular, their role in the transition from innate to acquired immunity and in amplification of polarized responses in more detail and emphasis will be on selected molecules and pathologies used as a paradigm.

AGONISTS AND RECEPTORS Chemokines represent a large superfamily of small proteins classified into four distinct families according to cysteine residues' relative position in the N-terminal portion of the molecule. In CC or 13 chemokines, the most abundant family with 25 molecules in humans, the first two Cys residues are adjacent (Table 47.1). Although the overall sequence identity of chemokines is less than 20%, these molecules share a common structural organization constrained by disulfide bonding between the first and third and second and fourth cysteine residues, with a structurally disordered N-terminal loop followed by three antiparallel 13 sheets and a C-terminal ~ helix (Zlotnik and u 2000). The first set of CC chemokines identified represented a functional homogeneous group of molecules, including the monocyte chemotactic proteins (CCL2, CCL8, CCL7 and CCL13), the macrophage inflammatory proteins (CCL3, CCL3L1 and CCL4), CCLll and CCL5. These molecules, clustered on chromosome 17, shared inducibility in inflammatory

conditions and chemotactic activity on monocytes, T lymphocytes and eosinophils but not neutrophils, and for these reasons they were traditionally associated with leukocyte infiltrate in chronic inflammation. At the other site of the system, CXCL8 and related molecules were associated with neutrophil recruitment during acute events (Rollins, 1997). This simplified scheme has been overcome by the recent discovery of a second set of CC chemokines, such as CCL19, CC21, CCL20, and others. These constitutive chemokines, encoded by different loci, are active on different leukocyte populations and have a role in physiologic events during the development of the immune system, such as thymocyte development, lymphocyte homing and dendritic cell migration to secondary lymphoid organs. Consequently, the spectrum of target leukocytes for CC chemokines now includes virtually all leukocyte populations with the possible exception of neutrophils (Mackay, 2001). In general, CC chemokines are redundant in their action on leukocytes. Any given leukocyte population usually responds to different molecules, in most cases acting on different receptors, and most chemokines are active on multiple leukocyte populations (Table 47.2). The interaction of chemokines is also characterized by considerable promiscuity, with most receptors interacting with multiple ligands, and most ligands with more than one receptor. These properties, more pronounced for inflammatory CC chemokines involved in pathologic conditions, confer robustness to the system (Mantovani, 1999) and account for the relatively faint phenotype of knockout mice of these sets of chemokines, when compared with constitutive chemokine knockout mice. The eponymous function of chemokines is to elicit directional migration of leukocytes, and the traditional view of chemokines as mediators of leukocyte accumulation at sites of inflammation is still valid. However, it is now clear that CC chemokines also affect leukocyte functions other than directional migration, as discussed later on, and also act on other cell types, such as fibroblasts and endothelial cells, affecting functions of relevance both in normal tissue growth and disease, such as collagen production, angiogenesis and proliferation of hematopoietic precursors (Lloyd et al., 1997; Broxmeyer et al., 1999). Chemokines elicit their biological activities through

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interaction with seven transmembrane domain proteins which form a distinct group of structurally related proteins within the GTP-binding proteincoupled receptor superfamily. The sequences of chemokine receptors show 25 to 80% amino acid identity, suggesting the presence of a common ancestor belonging to the family of chemotactic receptors. Indeed, the first chemokine receptors were identified in the early 1990s using reverse transcriptase-PCR strategies with degenerate primers designed on conserved regions of classical chemoattractant receptors. However, many other G protein-coupled peptide receptors also have approximately 25% amino acid identity with chemokine receptors, indicating that the structural boundary is not clear and that more than overall sequence identity, relatedness is established by structural features more frequently observed in chemokine receptors than the unrelated seven transm e m b r a n e domain receptors. These include a length of 340-370 amino acid, an acidic N-terminal segment, a conserved sequence (LxxLxxDLLF) in the second transmembrane domain, a conserved sequence (DRYLAWHA or subtle variations of it) in the second intracellular loop, a short basic third intracellular loop and the presence in most cases of one cysteine residue for each of the four extracellular domains (Murphy et al., 2000). Eleven CC chemokine receptors have been molecularly defined to date, with a promiscuous pattern of

ligand recognition and differential expression and regulation in leukocytes (Table 47.2). Receptors for inflammatory chemokines (CCR1 to CCR5 and CCR8) were first identified. This set of receptors is encoded by genes in a cluster on chromosome 3p21, recognizes CC chemokines associated with monocyte and lymphocyte recruitment in chronic inflammation, and includes most of the HW co-receptors described (Berger et al., 1999). CCR1 was the first CC receptor identified, described originally as the MIP-la/RANTES receptor. Expressed on a particularly large panel on different leukocytes, it is in fact one of the most promiscuous chemokine receptors, with at least nine ligands identified. A clear indication of CCRI's role in disease has still to be established. Although the knockout mouse has increased susceptibility to pathogens, the fact that in the mouse this receptor is associated with neutrophil recuitment, as substitution of CXCR1, is a confounding element (Gao et al., 1997). On the other hand, CCR2 is the only CCL2 receptor identified so far and the only receptor for all four monocyte chemotactic proteins. It presents a more restricted leukocyte expression profile, and its role in monocyte recruitment in pathologic conditions and in atherosclerosis has been clearly defined in knockout models (Boring et al., 1998). CCR3 expression on basophils, eosinophils and TH2and the selective interaction with the three eotaxins (CCLll, CCL24 and CCL26) are a clear indication of the poten-

TABLE 47.2 Ligand and leukocyte specificities for h u m a n chemokine receptors Systematic name

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Main ligands

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6q27 17q12-21 3p22-p23 3p21.3-22 17q21.1-q21.3 3p22

CCL3, CCL3L1, CCL5, CCL7, CCL8, CCL14, CCL15, CCL16, CCL23 CCL2, CCL7, CCL8, CCL13, CCL16 CCL5, CCL7, CCLll, CCL13, CCL15, CCL24, CCL26 CCL17, CCL22 CCL3, CCL3L1, CCL4, CCL5, CCL8, CCL14 CCL20 CCL19, CCL21 CCL1 CCL25 CCL27, CCL28 CCL19, CCL21, CCL25

Thy, NK, TH2,Tc2 TM Ba, Thy, T m, Tcl, iD(~, ' Mo T M, B, iDC Thy, T N, B, mDC Thy, TH2, Mo Thy, T M,B TM T, iDC

NK, natural killer cells; Mo, monocyte-macrophages; Ba, basophils; Eo, eosinophils; Neu, neutrophils; Thy, thymocytes; TH, T helper; Tc, T cytotoxic; TM,T memory; TN,T naive; iDC, immature dendritic cells; mDC, mature dendritic cells. THE CYTOKINES AND CHEMOKINES

REGULATION OF P R O D U C T I O N : CONSTITUTIVE VERSUS I N D U C I B L E CC C H E M O K I N E S

tial role of this receptor in allergic inflammation, including asthma and antihelminthic host defence. CCR3, CCR4 and CCR8 characterize TH2 cells, as opposed to CCR5 expressed preferentially on TH~cells. These receptors are involved in lymphocyte traffic and polarized responses, as will be discussed later on. Owing to its predominant role in HIV infection, CCR5 is at present the best-defined CC receptor. Ligands and expression profile have been defined both in the human and mouse setting, and appear to be similar. Other than TH1cells, CCR5 is also expressed in immature dendritic cells, being down-regulated during maturation, as for all the CC receptors for inflammatory chemokines, and in monocytes. The presence in the general population of an allelic variant with a 32-bp deletion in the ORE resulting in the absence of CCR5 expression in homozygotes, which appear healthy, indicates that CCR5 functions are probably performed by other receptors. However, its role in disease has been demonstrated in knockout mice, which show subtle defects under specific pathologic conditions (Huffnagle et al., 1999). A second set of CC receptors includes molecules encoded outside the 3p21-22 cluster that are mainly involved in regulation of leukocyte trafficking in physiologic conditions. CCR6 and CCR7 play a crucial role in different steps of dendritic cells, the first being crucial for skin homing of immature Langerhans-type dendritic cells, the second being up-regulated after dendritic cell activation and driving the mature cell to lymph nodes. Sharing ligands with CCR7, CCR11 might also have a role in this process (Gosling et al., 2000). CCR9 and CCR10 are associated with T-cell development in the thymus and with mature T-cell homing in different regions (Wurbel et al., 2001). Two CC chemokine receptors, termed DARC and D6, have been reported to bind chemokines with high affinity with no subsequent signaling activity. DARC binds most CC and CXC chemokines, while D6 binding properties are restricted to CC inflammatory chemokines. Both receptors have a typical seven transmembrane domain architecture, with low but significant sequence homology to chemokine receptors. Interestingly, alignment of D6 and DARC with functional chemokine receptors highlighted few distinct residues conserved in all signaling chemokine receptors and modified in both binding molecules involved in ligand-dependent receptor activation

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(Mantovani et al., 2001). Although in the absence of signaling and chemotactic activity these molecules cannot be included in the list of CCRs, the structural properties and binding profiles indicate that they can be viewed as 'silent' receptors. Different functional hypotheses for these receptors have been formulated, including presentation, transport or scavenging of the ligands. In consideration of the high expression level in erythrocytes and the wide range of ligands, DARC was first proposed to be involved in maintaining a tissue-to-blood chemokine gradient by clearing chemokines from the blood stream (Horuk et al., 1993). However, the existence of an erythroid-specific DARC promoter variant allele resulting in the absence of DARC expression on erythrocytes of healthy DARC-negative subjects argued against this hypothesis. It was subsequently found that DARC is expressed in all individuals under the action of a different promoter in various nonerythroid regions, and that it can act as a transendothelial transporter for the ligand. A similar hypothesis has also been formulated for D6, in particular after demonstration of D6 expression on lymphatic vessels (Nibbs et al., 2001). However, we observed that D6 interaction with ligands results in chemokine internalization and degradation (manuscript in preparation). For this reason, we propose that D6, and possibly other chemokine orphan receptors, might functionally act as 'structural decoy receptors', being able to interact with and scavenge the ligand without giving rise to activating intracellular signals but competing with signaling-competent receptors and removing chemokines from the system when no longer required.

REGULATION OF PRODUCTION: CONSTITUTIVE VERSUS INDUCIBLE CC CHEMOKINES A useful classification of chemokines, and more so of the most numerous CC family, distinguishes between molecules that are produced in a tonic way (constitutive) and those produced in response to diverse signals (inducible or inflammatory CC chemokines) (Mantovani 1999; Zlotnik and Yoshie 2000) (Figure

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FIGURE 47.1 Functional classification of CC chemokines.

47.1). Prototypic molecules of the constitutive CC chemokine realm are CCL14, present in normal plasma, and CCL18, constitutively expressed by dendritic cells. Prototypic molecules of the inducible CC chemokine realm are CCL2, CCL3, CCL4, CCL5 etc. The general significance of constitutively expressed CC chemokines is to guide the normal traffic of leukocytes under normal conditions. For instance, CCL27 is probably important for regulation of traffic to cutaneous sites. CCL21 and CCL19, expressed by lymphatic endothelium and by high endothelial cells respectively, are important for guiding migration of lymphocytes and dendritic cells in lymphoid organs. The presence in normal plasma of substantial amounts of CCL14, CCL15 and CCL16 (the HCCs), interacting with receptors widely expressed on peripheral blood leukocytes (CCR1, CCR5) has as yet unknown significance. The general significance of inducible chemokines is to regulate recruitment of leukocytes on demand, in response to immunological, inflammatory and infectious signals. These two realms overlap in terms of molecules and pathology. As discussed below, in neoplastic disorders constitutive expression of inducible chemokines is observed. Moreover, a number of molecules behave both as constitutive and inducible chemokines. For instance, CCL22 was initially described as a chemokine constitutively expressed in certain cell types, most notably dendritic cells, and in certain lymphoid organs, in particular the thymus (Mantovani et al., 2000a). Subsequent work,

prompted by the recognition that this molecule preferentially attracted polarized type IIT cells, has shown that CCL22 is expressed in a regulated way. Expression of inducible chemokines is stimulated by signals which interact with diverse cellular receptors, including receptors involved in innate immunity, pattern recognition receptors such as members of the Toll family, the T-cell receptor and co-stimulatory molecules for lymphocytes. As discussed below, chemokines are part of the circuits that are involved in the generation and amplification of polarized type I and type II responses. It is therefore not surprising that master cytokines that activate polarized responses differentially regulate chemokine production (Plate 47.2 see Plate section). For instance, the type II master cytokines, IL-4 and IL-13, induce production of agonists which interact with receptors that are preferentially expressed on polarized type II T cells, including CCL22 and CCL17 (agonists for CCR4), CCLll (agonist for CCR3) and CCL1 (CCRS). Conversely, IFN7 as expected inhibits production of CCL22 in different cell types and induces expression of CXCR3 agonists (Rollins 1997; Mantovani 1999; Zlotnik and Yoshie, 2000) as well as of CX3CL1. CX3CL1 expression, the last identified chemokine involved in polarized responses (Fraticelli et al., 2001), is induced by IFN7 and TNF and inhibited by IL-4 and IL-13. Hence, using CCL22 as a paradigm, this chemokine is induced by generic stimuli representatives of interaction with microbial pathogen (LPS) or immunocompetent cells (CD40L). In addition, the master cytokines, IL-4/IL-13 and IFNT, have reciprocal and divergent effects on production of this chemokine involved in the amplification of polarized type II responses (Mantovani et al., 2000b).

ROLE OF CD26/DPP IV IN CHEMOKINE PROCESSING An additional level of regulation of chemokine function is represented by modifications at the NH2terminus. Chemokines of both CXC and CC subfamilies are naturally posttranslationally modified. For instance, two predominant forms of CXCL8 were described to possess a different activity in neutrophil activation, and truncated forms of several CC chemokines were purified by cell supernatants and

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biological fluids (Van Damme et al., 1999). These truncations are due to the action of several proteases including attractin, plasmin, urokinase plasminogen activator and CD26 (Van Damme et al., 1999). The role of dipeptidyl-peptidase W, also known as CD26, in chemokine processing has recently been the focus of great interest (DeMeester et al., 1999; Van Damme et al., 1999). CD26 was originally identified as a marker of activated memory T lymphocytes (Morimoto and Schlossman, 1998; DeMeester et al., 1999). However, CD26 is expressed in several cell types, including endothelial and epithelial cells. CD26 is a cell membrane-associated protein that is also found in a soluble form in seminal fluid, urine and plasma. This protein exerts a unique peptidase activity, it cleaves dipeptides from the NH2-terminus of proteins having a Pro or Ala residue at the penultimate position. Several chemokines possess a proline residue in the NH2 region in position 2. However, some of them, like MCP-1, -2, -3 and -4 are protected from CD26 degradation by a pyroglutamate at the NH2-terminus which protects the protein by degradation. In contrast, other chemokines can be effectively processed by the enzyme (Lambeir et al., 2001), and the biological output of this cleavage is unpredictable. CXCL6 a CXC chemokine, is cleaved, but its biological activity remains unaffected. However, for most chemokines (CCL5, CXCL12, CCL22 and CCLll) truncation by CD26 is accompanied by reduced, or somewhat altered, receptor binding and signaling. For all these chemokines a Pro and not Ala residue at the penultimate position is involved. An exception is CCL22 which is processed beyond this cleavage site. Very often, CD26-processed chemokines (e.g. CXCL12 and CCL11) not only lose their biological activity but also start to function as receptor antagonists being able to inhibit the biological activity of intact proteins. Occasionally, the processed chemokine has a more complex biological behavior. CCL5 (3-68) functions as a receptor antagonist for CCR1 and CCR3, but shows an increased affinity for CCR5 (DeMeester et al., 1999). Similarly, CCL3L1 (3-70) was 10-fold more efficient and 30-fold less efficient than full-length protein for binding to CCR5 and CCR3, respectively (Struyf et al., 2001). The availability of new analytical techniques able to identify full-length proteins, as well as processed chemokines in biological fluids, will allow

the clarification of the role of CD26 in chemokine biology.

REGULATION OF RECEPTOR EXPRESSION AND COUPLING CC chemokines are regulated not only by changing the levels of agonist production, but also by regulating expression of the appropriate receptors. One of the first observations made on this point was that monocytes exposed to bacterial LPS showed a dramatic down-regulation of the receptor for CCL2, CCR2 (Sica et al., 1997; Moser and Loetscher, 2001). This effect was associated with destabilization of the transcript, and was not dependent on induction of the agonist. Subsequent work has extended this observation to other proinflammatory signals, including TNF, IL-1 and IFN7 as well as to other cell types such as dendritic cells (see below) and certain chemokine receptors on activated T and NK cells. These results suggest that down-regulation of certain inflammatory chemokine receptors (CCR2 most dramatically, CCR5, CCR1) may deliver a stop signal to recruited mononuclear phagocytes to focus their action at sites of infection and inflammation (Figure 47.3). When these proinflammatory signals leak into the systemic circulation, by down-regulating CCR2 expression, they may provide a negative signal to inhibit excessive mononuclear phagocyte recruitment at sites of inflammation and tissue damage.

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FIGURE 47.3 Down-regulation of inflammatory chemokine receptors by primary proinflammatory molecules as a stop signal. For simplicity only CCR2 is shown.

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Reciprocally, anti-inflammatory signals such as glucocorticoid hormones and IL-10 were shown to increase expression of certain chemokine receptors, including CCR2 and CCR5 (Sozzani et al., 1998a; Penton-Rol et al., 1999; Moser and Loetscher, 2001). Hence, pro- and anti-inflammatory signals have reciprocal and divergent effects on expression of certain chemokine receptors in human mononuclear phagocytes and this may serve as a strategy to finely tune the action of chemokines. The results described so far refer to canonical cellular targets for CC chemokines, mononuclear phagocytes. It was also found that non-canonical cellular targets are rendered responsive to chemokines by microenvironmental signals. IFN7 rendered neutrophils responsive to a series of CC chemokines, in particular CCR1 agonists (Bonecchi et al., 1999). Mononuclear phagocytes express CXCR1 and CXCR2 but show little functional response. When cells are exposed to IL-4 and IL-13, increased receptor expression and coupling render these cells extremely sensitive to CCL8 and related CXC chemokines. Therefore, microenvironmental signals tune and shape the action of CC chemokines, by regulating receptor expression and coupling. IL-10 tends to increase expression of certain inflammatory chemokine receptors, such as CCR2 and CCR5 (Sozzani et al., 1998a). The significance of this observation may in fact relate to the effect of this cytokine when combined with primary proinflammatory signals (D'Amico et al., 2000). It was observed that IL-10 blocks down-regulation of inflammatory chemokine receptors induced by LPS alone or in combination with IFN~/in monocytes and dendritic cells. However, monocytes and dendritic cells exposed to a combination of IL-10 and LPS, while showing high levels of CCR2 and CCR5, did not migrate in response to appropriate agonist and showed defective activation of signal transducing events. Inflammatory chemokine receptors in cells exposed to a combination of LPS and IFN? retain the ability of binding and sequestering agonists. Evidence was obtained that chemokine scavenging may also occur in vivo in tissues where dendritic cells exposed to a combination of IL-10 and TNF are present. Hence, in an inflammatory environment dominated by IL-10, cells expressing inflammatory chemokine receptors are set in a chemokine scavenging, anti-inflammatory mode. It was therefore suggested that these chemokine recep-

tors act as functional decoy receptors for chemokines. More generally it has been suggested that nonsignaling 'silent' receptors (see above) are decoy receptors for chemokines, including CC molecules (Mantovani et al., 2001).

TRANSITION FROM INNATE TO ADAPTIVE IMMUNITY: DENDRITIC CELLS Dendritic cells (DC) are potent antigen-presenting cells with unique ability to capture antigens and to induce T- and B-cell response (Banchereau et al., 2000). Chemokines, and especially CC chemokines, regulate DC trafficking and localization. Immature myeloid DCs express functional CCR1, CCR2, CCR5, that are probably responsible for their migration to the site of immune response. Blood plasmacytoid DCs express a pattern of chemokine receptors similar to that of myeloid DCs. However, most chemokine receptors of plasmacytoid DCs, in particular those for inflammatory chemokines, are apparently not functional in circulating cells (Penna et al., 2001). Lymphoid cells purified from skin or generated in vitro from CD34 + precursors are characterized by the expression of CCR6, the receptor for CCL20 in addition to the receptors expressed by mono-DCs (Power et aL, 1997). CCR6 also interacts with defensins which have agonist activity for DCs (Yang et aL, 2000). In the mouse, myeloid DCs express CCR6 and localize to the subepithelial dome of Peyer's patches in response to CCL20 which is strongly expressed by the overlying epithelium. CCR6-/- mice have defective accumulation of DCs in gut mucosal tissues and defective response to orally administered antigens. Thus, increasing evidence points to a distinct role of CCL20/CCR6 in recruitment of DC towards the mucosal surfaces (Cook et al., 2000). Monocyte DCs also express two orphan receptors ChemR23 (Samson et al., 1998), and HCR (Otero and Sozzani, unpublished). The role of these two receptors in DC biology is still unknown. Maturation of DCs is associated with the inhibition of chemotactic response to inflammatory chemokines and the up-regulation of CCR7. CCL19 and CCL21, the ligands of CCR7, are specifically expressed in T cell-rich areas of tonsils, spleen and LN, where mature DCs home, to become inter-

THE CYTOKINES A N D C H E M O K I N E S

LYMPHOCYTE TRAFFIC AND POLARIZED RESPONSES digitating DCs (Cyster, 1999; Allavena et al., 2000). The crucial role of CCR7 is clearly reflected in mice deficient for this receptor and the two ligands. Overall, these findings provide a model for DC trafficking in which inflammatory chemokines acting through CCR1 and CCR5 or CCR6, function as signals to localize DC precursors to peripheral tissues. After antigen uptake, immune/inflammatory stimuli induce DC maturation and loss of responsiveness to the inducible cytokines locally produced. This unresponsiveness may play a permissive role for DCs to leave peripheral tissues. Meanwhile, the slower upregulation of CCR7 prepares the cells to respond to CCL19 and CCL21 expressed in lymphoid organs. DCs also represent a source of chemokines in vitro and in vivo. In vitro, immature DCs constitutively produce CCL22, CCL9/10 and CCL18 (Allavena et al., 2000). Thymic DCs selectively express CCL25, a CC chemokine active on thymocytes, macrophages and DCs. Production of chemokines by DCs is strongly increased when these cells are induced to differentiate by proinflammatory stimuli (e.g. LPS, TNF) or engagement of CD40. In vitro, mature DCs produce conspicuous amounts of CCL2, CCL3, CCL5 and CXCL8 (Sallusto et al., 1998; Vulcano et al., 2001). Mature DCs also produce very high concentrations of MDC and TARC (Vulcano et al., 2001). In vivo, MDC was detected by in situ hybridization in mature DCs and the protein is strongly produced by CD83 + cells in the skin of atopic dermatitis patients (Vulcano et al., 2001). CX3CL1 and CXCL16, two chemokines present in both membrane-anchored and soluble forms are produced by mature DCs (Kanazawa et al., 1999; Matloubian et al., 2000). CXCL13 is produced by follicular DCs and germinal center DCs and is likely to play a role in DC interaction with B and T lymphocytes (Vissers et al., 2001). DC-derived chemokines are believed to contribute to the recruitment of precursor cells and immature DCs at peripheral sites of inflammation (Sallusto et al., 2000; Cyster, 1999; Allavena et al., 2000). Furthermore, within lymph nodes, chemokines may also play a role in T- and Bcell localization and in DC-T cell interaction (Cyster, 1999; Banchereau et al., 2000).

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LYMPHOCYTE TRAFFIC AND POLARIZED RESPONSES Homeostatic CC chemokines play a role in regulating the normal traffic of lymphocytes in lymphoid organs (Luther and Cyster, 2001; Moser and Loetscher, 2001). The CCR7 receptor is expressed on mature DCs (see above), naive T cells and a subset of memory T cells (central memory T cells) (Sallusto et al., 1999). CCR7 is recognized by two ligands, CCL21, present in two forms in the mouse differing by one amino acid, serine-leucine at position 65, and CCL19. CCL21 is expressed on lymphatic endothelial cells whereas CCL19 is expressed by various cell types, including high endothelial venules. Analysis of the mouse mutant pit and of CCR7 -/mouse has given results consistent with a nonredundant role of this CC chemokine receptor in regulating traffic of lymphoid cells and DC in lymphoid organs (F6rster et al., 1999; Gunn et al., 1999). As discussed above, gene targeting has also revealed unequivocally a role for CCR6 in the regulation of DC traffic in the mucosal compartment. The CC chemokines CCL17 and CCL27 are important for the traffic of skin-homing T lymphocytes (Campbell et al., 1999; Morales et al., 1999). CCL17 recruits CLA+ T cells, which are the predominant type present in the skin. CCL17 is expressed on skin endothelial cells. Moreover, CCL27, a chemoattractant expressed widely in the skin, being produced by keratinocytes, is active on CLA+ T cells. Therefore, this tissue-specific CC chemokine can direct migration of the CLA+ T-cell subset to this anatomical site. There is compelling evidence that a set of chemokines are involved in polarized TH1/TH2 responses (Mantovani, 1999; Luther and Cyster, 2001; Moser and Loetscher, 2001). Polarized TH1 and TH2 cells express differential chemokine receptors. Typically, the CC chemokine receptors CCR3, CCR4 and CCR8 have been associated with a TH2 phenotype whereas functional CXCR3 and CCR5 are preferentially expressed on polarized type I T cells (Plate 47.2). CCR3 ligands also attract eosinophils and basophils, crucial for polarized type II responses. Differentially expressed chemokine receptors are not markers for polarized T cells, in that there is no absolute association between chemokine receptor expression and cytokine repertoire of polarized T cell populations. In contrast,

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the seven transmembrane domain receptor CRTH2 has been shown to be more closely associated with the TH2 phenotype than are chemokine receptors. For instance, CCR4, while expressed at much higher levels in polarized TH2 cells, is induced in TH1 cells following activation and is also expressed in non-polarized T-cell populations. Moreover, CCR4 has been suggested to be involved in homing to the skin. As discussed above and described in Plate 47.2 consistent with the role of polarized T-cell responses, agonists for receptors expressed differentially in polarized T cells are differentially induced/inhibited by IL-4, IL-13 and IFN. For instance, the CCR4 agonists CCL17 and CCL22 are induced by IL-4 and IL- 13 and are inhibited by IFNT. A CCR4 -/- mouse has been generated, but no evidence for alteration in polarized responses has been observed. However, antibody against MDC blocked recruitment of T cells in a classic model of airway hyperreactivity. No abnormalities in airway hyperreactivity were observed in CCR3 -/- mice. In constrast, CCR8 -~- mice were protected against higher airway hyperreactivity. Recent careful analysis of chemokine receptors expressed in T cells in asthma has yielded results consistent with a role of this molecule in allergic inflammation (Panina-Bordignon et al., 2001). It was found that in allergic asthma CCR3 is rarely expressed in T cells, unlike CCR4 and CCR8. Collectively, these results suggest that chemokines play a key role in the induction and amplification of polarized responses and may represent an important target for therapeutic intervention. In addition to playing a role in the effector phase of polarized responses, chemokines may be important in their induction. Analysis of responses to a parasite component has suggested a key role for CCR5 expressed on DCs not only in their migration but also in the induction of IL-12 (Aliberti et al., 2000). Studies in CCL2 -/- mice have indicated that this chemokine may be important for the induction and expression of polarized type II responses. Interestingly, data in CCR2 -/- mice have pointed in the opposite direction as far as polarized responses are concerned (Bonecchi et al., 1999; Gu et al., 2000). In contrast, consistent results between gene targeting of the agonist and of the receptor have been obtained in terms, for instance, of susceptibility to atherosclerosis. Indeed, in a redundant and promiscuous system in which several agonists interact with one receptor, inactivation

of one of them is not necessarily equivalent to receptor blockade. Receptor inactivation may block one pathway which scavenges the agonists. Therefore, in the MCP system, this may result in increased concentration of members of a family such as MCP-3, which in addition to interacting with CCR2 interacts with CCR3, a receptor expressed on a subset of polarized TH2 cells as well as on eosinophils and basophils. This may explain the apparent discrepancy in terms of influence on polarized responses obtained between studies in agonist CCL2 and receptor (CCR2) genetargeted mice.

TUMORS AS A PARADIGM OF THE ROLE OF CC CHEMOKINES Most, if not all, tumors produce chemokines of the two major groups, CC and CXC (Balkwill and Mantovani, 2001). Compelling evidence in murine models and in human tumors suggests that CCL2 and related CC chemokines such as CCL5 are major determinants of macrophage and lymphocyte infiltration in melanoma, in carcinoma of the ovary, breast and cervix, and in sarcomas and gliomas (Sciacca et al., 1994; Negus et al., 1995; Riethdorf et al., 1996; Luciani et al., 1998; Valkovic et al., 1998; Luboshits et al., 1999). In Hodgkin's disease the malignant Reed-Sternberg cells express the TH2 attracting chemokines CCL22 and CCL17 (Cossman et al., 1999; van den Berg et al., 1999) and the chemokine eotaxin, produced by stromal elements, correlates with eosinophil infiltration (Jundt et al., 1999; Mazzucchelli et al., 1999). Chemokine production by tumor cells may reflect constitutive gene expression or activation by autocrine/paracrine loops, as shown for Fas/FasL in brain tumors and IL-6 in cervical neoplasia (Hess et al., 2000; Choi et al., 2001). Chemokine receptors are expressed by both infiltrating leukocytes and tumor cells. The former may lose receptor expression once they are exposed to cytokines in the tumor microenvironment, as shown for CCR2 on TAM in ovarian cancer (Sica et al., 2000). In the murine and human tumors studied, TAM have a skewed type II phenotype. They do not produce IL-12 and NF~cB activation is lacking. TAM spontaneously release conspicuous amounts of IL-10 and TGF[3 (Kim et al.,

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TUMORS AS A PARADIGM OF THE ROLE OF CC CHEMOKINES 1995; Maeda and Shiraishi, 1996; Sica et al., 2000a). Autocrine production of IL-10 may be responsible for the phenotype of TAM (Sica et al., 2000b). The mechanisms responsible for the polarization of TAM to a type II phenotype are a matter of speculation. A TH2/Tc2 dominated T-ceU response in situ, with production of IL-4 and IL-13 (Huang et al., 1995; Sozzani et al., 1998b; van den Berg et al., 1999), would drive a type II inflammatory response. Some chemokines, including CCL2, induce IL-10 in macrophages. Moreover, data in knockout mice suggest that CCL2 polarizes immunity in a TH2 direction (Gu et al., 2000). Chronic exposure to high chemokine concentrations in the tumor microenvironment may set in motion a chemokine-centred vicious circuit, leading to skewing towards a type II inflammatory response (Sica et al., 2000). Some viruses encode chemokines, chemokine inhibitors and chemokine receptors. Of particular interest is human herpesvirus 8 (HHV8), which is involved in the pathogenesis of Kaposi's sarcoma (KS) and body cavity lymphoma. In addition to encoding a constitutively active chemokine receptor, which acts as a dominant oncogene (Cesarman et al., 2000; Yang et al., 2000), HHV8 contains three chemokines, called vMIP-I, vMIP-II and vMIP-III. These three chemokines are selective attractants of polarized type II T cells and interact with chemokine receptors (CCR3, CCR4, CCR8) expressed on this population (Sozzani et al., 1998b; Endres et al., 1999; Stine et al., 2000; Weber et al., 2001). T cells infiltrating KS, which are predominantly CD8 +, have a skewed TH2 phenotype (Sozzani et al., 1998b). HHV-8 encoded chemokines thus might be a strategy to subvert immunity, by activating type II responses and diverting effective TH1 defense mechanisms (summarized in Plate 47.2). In terms of inflammatory reactions, neoplastic disorders constitute an apparent paradox. As discussed above, many, if not all, tumors produce inflammatory cytokines, chemokines and are infiltrated by leukocytes. However, neoplastic disorders are associated with a defective capacity to mount inflammatory reactions at sites other than tumors, and circulating monocytes from cancer patients are defective in their capacity to respond to chemoattractants (Snyderman and Cianciolo, 1984; Balkwill and Mantovani, 2001). Various factors originating in the tumor microenvironment may contribute to the systemic anti-

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inflammation associated with cancer. Chemokines leaking into the systemic circulation are likely to desensitize circulating leukocytes (Rutledge et al., 1995); elevated levels of TNF receptors and the type II decoy IL-1 receptor may buffer inflammatory cytokines; and tumors also produce anti-inflammatory cytokines such as IL-10 or TGF[3 (Kim et al., 1995; Maeda and Shiraishi, 1996; Sica et al., 2000b). On this basis, a defective capacity to mount a systemic inflammatory response in cancer patients coexists with continuous leukocyte recruitment at the tumor site. CC chemokines induce production of proteases, such as MMP and urokinase-type plasminogen activator in tumor cells and macrophages. These enzymes are important for invasion and it has been suggested that monocytes infiltrating the tumor tissue provide cancer cells with a ready-made path for invasion (counter current invasion theory) (Opdenakker and Van Damme, 1992). As described above, tumor cells may also express chemokine receptors. Appropriate chemokine agonists induce migration or proliferation of tumor cells, raising the interesting possibility that tumor cells may use chemokine gradients to spread around the body (Wang et al., 1990, 1998; Singh et al., 1994; Prest et al., 1999; Haghnegahdar et al., 2000; Muller et al., 2001). It has recently been found that breast carcinoma cells and melanoma cells express CCR7 and CXCR4 and these may be important for metastasis (Muller et al., 2001). Receptors such as CCR7, essential for lymphocyte and DC homing to lymph nodes, could play a similar role for lymphatic dissemination of certain carcinomas. Direct evidence for chemokines guiding the secondary localization of cancer has been obtained (Wang et al., 1998; Muller et al., 2001; Scotton et al., 2001; Schutyser et al., 2002). The finding of constitutive production of chemokines in tumors is consistent with the view that recruited leukocytes, macrophages in particular, provide a mechanism for tumor promotion directly or indirectly (Balkwill and Mantovani, 2001). The protumor function of chemokines is strictly related to the amounts produced. It has been shown that lowlevel CCL2 production renders non-tumorigenic melanoma cells capable of forming progressing tumor lesions (Nesbit et al., 2001). In contrast, forced expression of high levels of CCL2 and other CC

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cc CHEMOKINES

chemokines has caused tumor inhibition (Rollins, 1997; Mantovani, 1999; Nokihara et al., 2000; Zlotnik and Yoshie, 2000). In this context, expression of CC chemokines capable of attracting DCs such as CCL7 and CCL21 was associated with DC recruitment, activation of specific immunity and tumor regression (Fioretti et al., 1998; Vicari et al., 2000; Kirk et al., 2001; Nomura et al., 2001).

THE TRANSCRIPTIONAL PROGRAM ACTIVATED BY CC CHEMOKINES Various indications in the literature suggest that chemokines have a role in the development of different biological responses that goes beyond cell recruitment. For example, CXCR2 agonists support tumor growth through growth factor induction in malignant cells (Balentien et al., 1991), as also demonstrated for the related constitutively active GPCR ORF74 receptor encoded by HHV-8 (Sodhi et al., 2000). Chemokines have also been demonstrated to play a direct role in the definition of the cytokine milieu during both inflammatory (Jiang et al., 1992) and immune responses (Bandeira-Melo et al., 2000; Braun et al., 2000). Thus, chemokines not only support differential leukocyte recruitment, but also directly affect target cell functions. Gene chip-based gene expression profile analysis in chemokine-activated monocytes revealed that CC chemokines induce specific transcriptional programs in target cells (Table 47.3, and unpublished results), demonstrating that chemokine effects on target cells include induction of transcriptional events. CCL5 induced a significant fraction of TABLE 47.3 Comparison

of transcriptional profile induced by CCL5 a n d LPS in monocytes

A LPS

"~ ~ LPS

V LPS

ik CCL5

10 (0.2%)

16 (0.3%)

16 (0.3%)

~I l~ CCL5

84 (1.7%)

1385 (27.7%)

10 (0.2%)

0 (0%)

0 (0%)

0 (0%)

V CCL5

Monocytes were stimulated in non-adherent conditions for 2 hours with indicated agonists and transcriptional profile was analyzed using Affymetrix HuGene FL arrays, interrogating 5200 human genes. Percentages indicate the fraction of cell transcriptome regulated. A, upregulated; V, downregulated; ~1 I~, not regulated.

transcripts, which included inflammatory cytokines, indicating an active role for chemokines in the organization of the inflammatory reaction, and chemokines and their receptors, as previously reported (Fischer et al., 2001), suggesting an amplification and diversification cascade for leukocyte recruitment. CCL5activated transcriptional program also supports cell migration and tissue penetration, as demonstrated by induction of proteases and adhesion molecules acting on subendothelial structures. In contrast, consistent gene suppression was not observed after exposure to CCL5. Comparison with the classic inflammatory mediator LPS demonstrated that chemokines activate a specific transcriptional program partially overlapped with but clearly distinct from that induced by LPS.

CC CHEMOKINES AS THERAPEUTIC TARGETS Classic immunosuppressive and anti-inflammatory drugs are potent inhibitors of the production of certain chemokines. Active molecules include glucocorticoid hormones, FK506 and cyclosporin A (Poon et al., 1991; Zipfel et al., 1991; Mukaida et al., 1992; Wertheim et al., 1993; Loetscher et al., 1994; Sozzani et al., 1996). The compound 2-methyl-2[[1-(phenylmethyl)-lHindazol-3yl]methoxy] propanoic acid (bindarit) was recently found to inhibit chemokine production in a relatively specific way, although at high concentrations (Sironi et al., 1999). Bindarit inhibited MCP-1 production in human monocytes, with no effect on production of IL-8, RANTES and MIP-lu. Bindarit also blocked synthesis of TNF to some extent, but not of IL-1 or IL-6. Although recent results indicate that it inhibits p38 MAP kinase, the molecular mechanisms responsible for selectivity have not been defined. Agents that affect cholesterol metabolism can affect MCP-1 production. Lovastatin and mevastatin (two inhibitors of cholesterol production which block 3hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, inhibit MCP-1 production in mononuclear phagocytes and smooth muscle cells (Romano et al., 2000). The effect of lovastatin was reversed by the addition of mevalonate, as expected, considering its activity on HMG-CoA. Given the fundamental role of MCP-1 in the pathogenesis of atherosclerosis, it is

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REFERENCES

tempting to speculate that inhibition of chemokine synthesis, in addition to cholesterol lowering, is in fact a major part of these agents' activity in the prevention of acute myocardial infarction. NHz-terminal truncation or modification also resulted in the generation of potent antagonists for CC chemokine receptors. This is true for molecules such as CCL5, CCL2 and CCL7. Removal of eight residues at the N-terminus of MCP-1 produces an antagonist (Gong and Clark-Lewis 1995). CCL2 (9-76) is of special interest, as it kas been used in models of diseases such as arthritis, with appreciable therapeutic results (Gong et al., 1997). Expression of CCL5 in E. coli produced Met-CCL5, a functional antagonist or weak partial agonist for chemoattractant receptors. Similar results were obtained when CCL7 was expressed in Pychia pastoris. Met-CCL5 has been investigated in vivo in experimental models, such as arthritis and glomerulonephritis, and in models of airway inflammation (Plater-Zyberk et al., 1997). Aminoxypenthane modified CCL5 (AOP-RANTES) was an even better antagonist for several CC receptors (Simmons et al., 1997). AOP-CCL5 is internalized but does not elicit signal transduction and the receptor is prevented from being recycled. Peptide antagonists have proved valuable tools for chemokine pharmacology. They have provided structure-activity information essential for understanding ligand-receptor interactions. In addition, before the availability of knockout mice they validated chemokines as targets for pharmacological intervention in disease models. Finally, the discovery of N-terminal processing of chemokines by enzymes such as CD26 (see above), suggests that the generation of peptide antagonists may offer a strategy for fine tuning the chemokine system. Efforts have been made to develop small antagonists directed against HIV fusion co-receptors, particularly those most frequently used, CXCR4 and CCR5. TAK-779 antagonized CCR5, to a lesser extent CCR2B, and had no activity on CCR1, CCR3 and CCR4 (Baba et al., 1999). Small antagonists for CCR3 and CCR1, CCR2 and CCR5 (Hesselgesser et al., 1998; Dragic et al., 2000; Forbes et al., 2000; Huang et al., 2000; Liang et al., 2000; Mirzadegan et al., 2000; Proudfoot et al., 2000; Maeda et al., 2001; Naya and Saeki, 2001; Tagat et al., 2001) competitive or non-competitive, have been developed (e.g. see Sabroe et al., 2000;

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White et al., 2000). At least one CCR5 antagonist is currently undergoing clinical evaluation. It should be noted that studies appearing in the peer-reviewed literature in the field of chemokine antagonists represent the tip of the iceberg, most efforts not having surfaced as yet because of industrial strategies. Major stumbling blocks in the development of CCR antagonists include species specificity of receptor recognition or receptor function, crossreactivity with other GPCR, conformational heterogeneity of receptors. In addition to being drug candidates for diverse disorders ranging from allergy to HIV infection, small antagonists hold promise as tools to dissect the action of chemokines in vitro and in vivo.

CONCLUDING REMARKS CC chemokines are a complex system of molecules which affect a variety of hematopoietic and nonhematopoietic cell types. At least some of these molecules and their cognate receptors are interesting targets for pharmacological intervention (Mantovani et al., 2000a). Validation as pharmacological targets includes gene targeting (e.g. CCL2/CCR2, CCR1, CCR7, CCR8), usage of antibodies or antagonists (e.g. anti-CCL22, Met-CCL5), expression in human pathology (e.g. CCR4 and CCR8 in asthma), as discussed in this chapter. CC chemokine receptor antagonists have been developed (e.g. CCR5, CCR1) and are at various stages of preclinical or clinical development. The development of efficacious CC chemokine antagonists remains a 'holy grail' for the general field of cytokine pharmacology.

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THE CYTOKINES AND CHEMOKINES

(a)

CX3CR1 cxc

CCR2

Endothelialcells

Monocyte

~

. , ~ - - - ~

CCR5

CXCR3

Thl/Tcl (b)

~ ~"-----~

Endothelialcells

Fibroblast

CCR3

~

Eo/Ba/MC CCR3

~ DC

Monocyte

~

~

CCR4

~

CCR8

.~" -

_

.

.

.

.

.

Th2/Tc2 PLATE 47.2 Chemokines in polarized type I and type IIT cell responses. Eo, eosinophils; ba, basophils; MC, mast cells.