Stem cell factor and its receptor c-Kit as targets for inflammatory diseases

European Journal of Pharmacology 533 (2006) 327 – 340 www.elsevier.com/locate/ejphar

Review

Stem cell factor and its receptor c-Kit as targets for inflammatory diseases Laurent Reber ⁎, Carla A. Da Silva, Nelly Frossard EA 3771 «Inflammation and Environment in Asthma», Université Louis Pasteur-Strasbourg-I, Faculté de Pharmacie, Illkirch, France Accepted 13 December 2005 Available online 17 February 2006

Abstract Stem cell factor (SCF), the ligand of the c-Kit receptor, is expressed by various structural and inflammatory cells in the airways. Binding of SCF to c-Kit leads to activation of multiple pathways, including phosphatidyl-inositol-3 (PI3)-kinase, phospholipase C (PLC)-γ, Src kinase, Janus kinase (JAK)/Signal Transducers and Activators of Transcription (STAT) and mitogen activated protein (MAP) kinase pathways. SCF is an important growth factor for mast cells, promoting their generation from CD34+ progenitor cells. In vitro, SCF induces mast cells survival, adhesion to extracellular matrix and degranulation, leading to expression and release of histamine, pro-inflammatory cytokines and chemokines. SCF also induces eosinophil adhesion and activation. SCF is upregulated in inflammatory conditions both in vitro and in vivo, in human and mice. Inhibition of the SCF/c-Kit pathway leads to significant decrease of histamine levels, mast cells and eosinophil infiltration, interleukin (IL)-4 production and airway hyperresponsiveness in vivo. Taken together, these data suggest that SCF/c-Kit may be a potential therapeutic target for the control of mast cell and eosinophil number and activation in inflammatory diseases. © 2006 Elsevier B.V. All rights reserved. Keywords: SCF (stem cell factor); Kit; Inflammation; Mast cell; Eosinophil; Asthma

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Introduction . . . . . . . . . . . . . . . . SCF expression in the airways . . . . . . 2.1. Cellular origin . . . . . . . . . . . 2.2. Alternative splicing and proteolytic c-Kit expression in the airways . . . . . . 3.1. Cellular origin . . . . . . . . . . . 3.2. Alternative splicing and proteolytic SCF/c-Kit structure and interaction . . . . Regulation of SCF and c-Kit production . c-Kit signal transduction . . . . . . . . . 6.1. The MAP kinase pathway . . . . . 6.2. The PI3-kinase pathway . . . . . . 6.3. The PLC-γ pathway . . . . . . . . 6.4. The Src pathway . . . . . . . . . 6.5. The JAK/STAT pathway. . . . . . 6.6. Downregulation of c-Kit signalling 6.7. SCF-induced c-Kit internalization .

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⁎ Corresponding author. EA3771, Faculté de pharmacie, BP60024, 67401 Illkirch Cedex, France. Tel.: +33 3 90 24 42 00; fax: +33 3 90 24 43 09. E-mail address: [email protected] (L. Reber). 0014-2999/$ - see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2005.12.067

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Effect of SCF on inflammatory cells . . . . . . . . 7.1. Mast cells . . . . . . . . . . . . . . . . . . 7.1.1. SCF-induced mast cell development 7.1.2. SCF-induced mast cell survival . . . 7.1.3. SCF-induced mast cell chemotaxis . 7.1.4. SCF-induced mast cell adhesion . . 7.1.5. SCF-induced mast cell activation . . 7.2. Eosinophils . . . . . . . . . . . . . . . . . . 8. The SCF/c-kit complex as a target for inflammatory 8.1. Skin inflammation . . . . . . . . . . . . . . 8.2. Rheumatoid arthritis . . . . . . . . . . . . . 8.3. Allergic rhinitis. . . . . . . . . . . . . . . . 8.4. Asthma . . . . . . . . . . . . . . . . . . . . 9. Conclusion. . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction Stem cell factor (SCF), also termed Kit ligand, steel factor or mast cell growth factor is the ligand of the c-kit protooncogene product (Huang et al., 1990; Martin et al., 1990; Zsebo et al., 1990). It is a glycoprotein existing in both soluble and membrane bound forms, after alternative splicing and proteolytic cleavage (Anderson et al., 1991). W and Sl mice, which have, respectively, mutations on c-kit and scf loci, have defects in pigmentation and are anemic and sterile (Russell, 1979). Therefore, SCF has been first described as a pluripotent growth factor involved in the early stages of haematopoiesis (for review, see Broudy, 1997), as well as in the development and function of germ cells (for review, see Sette et al., 2000) and melanocytes (for review, see Yoshida et al., 2001). In addition, SCF may be implicated in inflammatory processes. This review will focus on SCF and c-Kit expression and regulation, the effect of SCF on mast cells and eosinophils, and summarize data from the literature showing the potential role of the SCF-c-Kit complex in inflammatory diseases. 2. SCF expression in the airways 2.1. Cellular origin The SCF gene is encoded at the steel (Sl) locus on human chromosome 12q22-q24 and murine chromosome 10 (Anderson et al., 1991). SCF is expressed in vitro by various cells from the airways, including the bronchial epithelial cells (Wen et al., 1996), bronchial subepithelial myofibroblasts (Zhang et al., 1996), lung fibroblasts (Kassel et al., 1998; Da Silva et al., 2003, 2002), bronchial smooth muscle cells (Kassel et al., 1999), endothelial cells (Heinrich et al., 1993), peripheral blood eosinophils (Hartman et al., 2001) and isolated human lung mast cells (de Paulis et al., 1999a; Zhang et al., 1998). 2.2. Alternative splicing and proteolytic cleavage SCF, also termed Kit ligand, is expressed as two isoforms after alternative splicing of the sixth exon (Anderson et al.,

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1991; Flanagan et al., 1991). The first SCF isoform is a 248 aa (45 kD) glycoprotein (SCF248) expressed at the cell membrane which is cleaved by proteases to generate a 165 aa (31 kD) soluble protein (sSCF or SCF165 ). The cleavage site is encoded by the sixth exon (Val-Ala-Ala-Ser, aa 163–166) (Pandiella et al., 1992; Majumdar et al., 1994). sSCF levels are about 3.3 ng/ml (177 pmol/L in terms of monomer) in human serum (Langley et al., 1993). The second SCF isoform is a 220 aa (32 kD) glycoprotein also expressed at the cell membrane. This form, lacking the sixth exon, remains membrane bound (mSCF or SCF220 ) but may also be shed by proteases to generate a soluble form (Huang et al., 1992; Pandiella et al., 1992) (Fig. 1). The secondary cleavage site used to generate the soluble form has been reported in the mouse, and is located at exon 7 (mutagenesis studies located it at or near Lys-Ala-Ala-Ser, aa 178–181). It seems to be used in the absence of the exon 6 primary cleavage site (Majumdar et al., 1994). The primary and secondary proteolytic cleavage sites of murine SCF have been mutated enabling the generation of cell lines producing only membrane-bound SCF, suggesting the absence of other major cleavage sites (Majumdar et al., 1994). Shedding of SCF248 involves a still unknown protease that might be a metalloprotease, as suggested by experiments using proteases inhibitors (Gallea-Robache et al., 1997). Recently, ADAM19 (A desintegrin and metalloprotease 19) and ADAM33 were found to cause shedding of SCF248 (Chesneau et al., 2003; Zou et al., 2004) in COS and HEK293 cells cotransfected both with ADAM19 or ADAM33 constructs and the full-length SCF248 plasmid. Additionally, the matrix metalloproteinase-9 (MMP-9) has been reported to cause shedding of active sSCF in hematopoietic stem cells, but the cleavage site has not been characterized (Heissig et al., 2002). The human mast cell chymase (EC 3.4.21.39) is also reported to cleave recombinant human SCF (rhSCF) in vitro (Longley et al., 1997; de Paulis et al., 1999b), although the sSCF protein generated is 7 aa shorter than sSCF spontaneously released by SCF producing cells. The sSCF / mSCF ratio varies considerably between cells and tissues (Huang et al., 1992). Human mast cells produce more

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and on human lung mast cells in the airways (Okayama et al., 1994). It has also been described on peripheral blood eosinophils (Yuan et al., 1997) and circulating basophils (Columbo et al., 1992). Expression of c-Kit has been reported on some structural cells, like human vascular smooth muscle cells (Hollenbeck et al., 2004), epithelial cells (Peters et al., 2003), and human umbilical vein endothelial cells (Aye et al., 1992; Broudy et al., 1994). These various c-Kit expressing cells also produce SCF, which may therefore act through an autocrine pathway (see Section 2.1). 3.2. Alternative splicing and proteolytic cleavage

Fig. 1. Alternative splicing of the sixth exon of mRNA produces two membranebound forms of SCF (SCF248 and SCF220). SCF248 is cleaved by proteases in the domain encoded by exon 6 (→) to produce a soluble 165 aa protein (SCF165 or sSCF). SCF220 or mSCF remains membrane-bound as it lacks the proteolytic cleavage site encoded by exon 6 but may also be shed in the region encoded by exon 7 ( ) to produce a soluble form.

Four different isoforms of c-Kit have been reported as a result of alternative splicing events. Alternative 5′ splice donor sites at the exon/intron junction of exon 9 lead to the presence or absence of a four amino acid sequence GNNK (glycineasparagine-asparagine-lysine, codons 510–513) in the juxtamembrane domain (Hayashi et al., 1991; Reith et al., 1991) (Fig. 2A). The GNNK+ / − variants are co-expressed in a variety of tissues in both human and mouse (Reith et al., 1991) with a predominant presence of the GNNK− isoform (Crosier et al., 1993; Furitsu et al., 1993; Piao et al., 1994; Zhu et al., 1994). The role of both isoforms is currently under investigation (see Section 6.4 and 6.7). An alternate splice acceptor site has been identified, in human but not mouse, resulting in the presence or absence of a serine residue in the cytoplasmic interkinase domain (S715) (Crosier et al., 1993) (Fig. 2A). As described for SCF, the c-Kit receptor can also be proteolytically cleaved, allowing shedding from the surface of hematopoietic cells, mast cells, and endothelial cells (Brizzi et

mSCF than sSCF (Welker et al., 1999), whereas the lung fibroblasts and the bronchial smooth muscle cells produce more sSCF than mSCF (Kassel et al., 1999; Kiener et al., 2000). Mauduit and collaborators studied the regulation of SCF mRNA splicing in murine Sertoli cells (Mauduit et al., 1999). At physiological pH, Sertoli cells preferentially express the sSCF. Lowering the culture medium pH, either by HCl addition or sodium bicarbonate withdrawal, causes a shift to formation of the mSCF isoform, occurring in a dose-dependent manner (Mauduit et al., 1999). The authors found an uncharacterized exon 6-binding complex responsible for the acidic-mediated splicing. Whether this mechanism occurs in SCF-producing cells in the airways is still unknown. 3. c-Kit expression in the airways 3.1. Cellular origin The c-Kit tyrosine kinase receptor is encoded at the white spotting (W) locus on human chromosome 4q11–q12 and murine chromosome 5 (Yarden et al., 1987; Qiu et al., 1988). c-Kit is principally expressed on hematopoietic stem cells,

Fig. 2. (A) Structure of the c-kit receptor. Four different isoforms of c-Kit exist as a result of alternative splicing events, and differ between presence or absence of a four amino acid sequence GNNK (codon 510–513) in the juxtamembrane domain and of S715 in the kinase insert. The reported tyrosine phosphorylation sites are indicated. (B) Binding of SCF homodimer leads to c-Kit dimerization and autophosphorylation. Nt: N-terminal; Ct: C-terminal.

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al., 1994a; Yee et al., 1993; Broudy et al., 1994; Turner et al., 1995). Soluble Kit is found in human serum at a concentration of 324 ng/ml (5.8 nmol/l), which is about 33-fold the reported concentration for sSCF (Wypych et al., 1995). This shedding occurs in the fifth immunoglobulin-like domain of c-Kit (Broudy et al., 2001), but the proteolycic cleavage site is unknown. Recently, tumor necrosis factor-α-converting enzyme (TACE; ADAM-17) was found to cause shedding of c-Kit in HEK-293 cells transfected with c-Kit cDNA. There was no difference in shedding between GNNK+ and GNNK− c-Kit isoforms (Cruz et al., 2004). 4. SCF/c-Kit structure and interaction SCF gene is composed of 8 exons. Exon 1 encodes a 5′ untranslated sequence and the first 5 aa of a 25 aa signal peptide. Exons 2–7 encode the extracellular domain. Exon 7 also encodes a 23 aa transmembrane domain, and exon 8 a short (36 aa) intracellular domain (Martin et al., 1990). sSCF is found as a noncovalently linked homodimer (Arakawa et al., 1991), which spontaneously dissociates and re-associates in solution (Lu et al., 1995). An in vitro study reveals that more than 50% of sSCF may be monomeric under physiological conditions (Hsu et al., 1997). The crystal structure of the core fragment of rhSCF expressed in E. coli has been reported. SCF presents a core composed of four α-helices and two β-strands. The SCF dimer associates in a symmetric ‘head to head’ structure (Jiang et al., 2000; Zhang et al., 2000). mSCF is also found as homodimers at the cell surface, and dimerization may be an essential step of mSCF/c-Kitmediated juxtacrine signalling (Tajima et al., 1998). The c-Kit receptor belongs to the subclass III of the tyrosine kinase receptor family, which also includes the platelet-derived growth factor receptor (PDGF receptor) and the macrophage colony stimulating factor receptor (M-CSF-R) (Yarden et al., 1987; Geissler et al., 1988; Qiu et al., 1988). The c-Kit gene spans over 80 kb of genomic DNA, and is composed of 21 exons. Exon 1 encodes the 5′-untranslated region and the signal peptide. Exons 2–9 encode the extracellular domain, exon 10 the transmembrane domain and exons 11–20 the intracellular domain (Qiu et al., 1988; Yarden et al., 1987). The extracellular domain (520 aa) consists of five immunoglobulin (Ig)-like domains (Fig. 2). SCF homodimer binding is confined to the first three Ig-like domain of c-Kit (Fig. 2B), and mediates c-Kit receptor dimerization (Lemmon et al., 1997; Broudy et al., 1998). Mutagenesis studies, immunochemical mapping and analyses of glycosylation reveal that the SCF receptor-binding site may include the first few N-terminal residues (Langley et al., 1994), the region between aa 79 and 95 (Matous et al., 1996; Mendiaz et al., 1996), and the region around Lys 127 (Matous et al., 1996). The c-Kit intracellular domain is composed of a tyrosine kinase domain split in two by an insert region. Dimerization of the receptor leads to autophosphorylation on several tyrosines in the cytoplasmic domain (Fig. 2). The crystal structure of the active kinase domain of c-Kit has been reported, and will facilitate the design of specific and potent c-Kit kinase inhibitors (Mol et al., 2003).

5. Regulation of SCF and c-Kit production SCF promoter activity is increased by cyclic AMP (cAMP) (Taylor et al., 1996a,b; Jiang et al., 1997; Grimaldi et al., 2003) in Sertoli cells, involving binding of a cAMP-induced factor in the proximal promoter region (Jiang et al., 1997), and a Sp1-binding region (Grimaldi et al., 2003). Interleukin (IL)-18 enhances SCF production in B16 murine melanoma cells through a pathway involving activation of the p38 mitogen and activated protein kinase (MAP kinase) (Hue et al., 2005). SCF production is increased by IL-1β, tumor necrosis factor-α (TNF-α) or phorbol 12-myristate 13-acetate (PMA) in vascular endothelial cells (Buzby et al., 1994), and lung fibroblasts (Da Silva et al., 2002). The IL-1β-induced SCF production is mediated through activation of the p38 and extracellular-regulated kinase1/2 (ERK1/2) MAP kinases, and the transcription factor NF-κB in human lung fibroblasts (Da Silva et al., 2003). Recently, the high-mobility group (HMG) A1 transcription factor was shown to positively regulate SCF promoter in breast and ovarian cancer cells (Treff et al., 2004). Taken together, these data show that SCF is upregulated in vitro by pro-inflammatory stimuli. On the other hand, glucocorticoids downregulate SCF production in human lung fibroblasts (Kassel et al., 1998; Da Silva et al., 2002, 2003), suggesting that SCF might be a good target for anti-inflammatory treatments. c-Kit expression is downregulated by various pro-inflammatory signals, such as IL-1β, TNF-α, and PMA, in human endothelial cells (Buzby et al., 1994). Granulocyte-macrophage colonystimulating factor (GM-CSF), IL-4 and IL-10 downregulate c-Kit expression in the human mast cell line HMC-1 (Sillaber et al., 1991; Welker et al., 2001; Mirmonsef et al., 1999). IL-1α and lipopolysaccharides (LPS) also downregulate the c-Kit expression in human endothelial cells, without any effect on c-Kit expression in progenitor CD34+ cells. The authors suggest SCF stops acting in an autocrine manner on the endothelium during an inflammatory state, to remain available as a hematopoietic growth factor for CD34+ cells (Konig et al., 1997). 6. c-Kit signal transduction Binding of SCF homodimers to c-Kit induces homodimerization and intermolecular tyrosine phosphorylation of the receptor, creating docking sites for a number of Src-homology2 (SH2)-containing signal transduction molecules (Fig. 2B and Fig. 3). 6.1. The MAP kinase pathway Growth factor receptor-bound protein-2 (Grb2) is an adaptor protein that binds to phosphorylated Y703 and Y936 of c-Kit (Thommes et al., 1999). Grb2 associates with the son-ofsevenless protein sos; this complex interacts with and activates the small G-protein Ras (Duronio et al., 1992), which leads to activation of Raf-1 (Miyazawa et al., 1991) and finally of the MAP kinases p38 (Ishizuka et al., 1999, 1998), ERK1/2 (Hallek et al., 1992; Ishizuka et al., 1999; Miyazawa et al., 1991) and c-

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phosphorylation and cell proliferation was downregulated (Fukao et al., 2002). 6.3. The PLC-γ pathway Most studies using sSCF failed to show phospholipase C-γ (PLC-γ) activation (Koike et al., 1993; Gommerman et al., 2000). A comparative study using sSCF and mSCF showed PLC-γ activation with mSCF but not sSCF (Gommerman et al., 2000), suggesting a differential effect for both forms of SCF in c-Kit signalling. PLC-γ associates with c-Kit in the absence of ligand in P815 transformed murine mast cells, where c-Kit is constitutively phosphorylated (Rottapel et al., 1991). PLC-γ associates with c-Kit after epidermal growth factor (EGF) stimulation in HEK293 cells overexpressing an EGF receptor-c-Kit chimera (Herbst et al., 1991). In addition, transfection of COS cells with a truncated form of c-Kit (tr-Kit) consisting of the kinase domain of Kit leads to activation of PLC-γ (Sette et al., 1998). The association site of PLC-γ seems to be the phosphorylated Y730 of c-Kit (Gommerman et al., 2000). 6.4. The Src pathway

Fig. 3. Signal transduction pathways of the c-Kit receptor. Homodimerized SCF binds to c-Kit, thus inducing c-Kit homodimerization and autophosphorylation, and the activation of different signalling pathways. Activation of the PI3-kinase, Src and the small G protein Ras induce activation of the different MAP-kinase pathways: ERK (extracellular-regulated kinase), p38 and JNK (Jun-N-terminal kinase). PI3-kinase also activates Akt/PKB. The Janus kinase (JAK) associates with phosphorylated c-Kit and activates the transcription factor STAT (Signal Transducers and Activators of Transcription). sos: son of sevenless; Grb-2: growth factor receptor-bound protein-2; MEK: MAP ERK kinase.

Jun N-terminal kinase (JNK) (Ishizuka et al., 1998). These MAP kinases are known to act on transcription factors activity, and thereby on gene transcription. 6.2. The PI3-kinase pathway Phosphatidyl-inositol-3 kinase (PI3-kinase) interacts with phosphorylated Y721 of c-Kit (Serve et al., 1994). SCF-induced PI3-kinase recruitment leads to Akt activation and to subsequent phosphorylation of the pro-apoptotic factor Bad. This phosphorylation inhibits Bad activity, thereby promoting cell survival (Blume-Jensen et al., 1998). Recently, Myb-immortalized haemopoietic cells (MIHC) were transduced to express WT or Y721F c-Kit (GNNK+ isoform). SCF-induced signalling in the Y721F mutant was insufficient to prevent a high rate of cell death. In the same study, the PI3-kinase inhibitor LY294002 inhibited SCF-induced survival of MIHC transfected with the GNNK+ isoform, in a dose-dependent manner (Young et al., 2006). PI3-kinase also mediates SCF-induced proliferation of bone marrow-derived mast cells (BMMC), by activating the small guanosine-triphosphate (GTP)-binding protein Rac1 and JNK pathways (Timokhina et al., 1998). This result was confirmed in PI3-kinase− / − BMMC, where SCF-induced JNK

SCF induces the activation of multiple Src (v-src avian sarcoma [Schmidt-Ruppin A-2] viral oncogene homolog) family members, including Src, Tec, Lyn and Fyn (BlumeJensen et al., 1994; Tang et al., 1994; Linnekin et al., 1997). The Src family associates with phosphorylated Y568 and Y570 in the juxtamembrane domain of c-Kit (Price et al., 1997; Ueda et al., 2002). Src kinase and PI3-kinase signalling pathways converge to activate Rac1 and JNK after SCF stimulation in BMMC, promoting cell proliferation (Timokhina et al., 1998). Reduction in the expression of the Src kinase Lyn using antisens oligonucleotides is accompanied by an inhibition of SCFinduced proliferation (Linnekin et al., 1997). In parallel, in Lyndeficient mast cells, SCF-induced proliferation is impaired, and transfection of murine mast cells with a dominant-inhibitory Lyn mutant inhibits SCF-induced growth (O'Laughlin-Bunner et al., 2001). SCF-induced gene transcription is also mediated by activation of members of the Src family kinases, leading to activation of the Ras/MAP kinase pathway (Lennartsson et al., 1999; Bondzi et al., 2000). The GNNK− isoform of c-Kit shows stronger activation of Src family kinases than the GNNK+ isoform (Voytyuk et al., 2003). 6.5. The JAK/STAT pathway SCF induces the activation of the Janus kinase (JAK)/Signal Transducers and Activators of Transcription (STAT) pathways. JAK2 associates with c-Kit and is phosphorylated after SCF stimulation (Brizzi et al., 1994b). JAK2 activation results in phosphorylation of STAT1α, 3, 5A and 5B (Brizzi et al., 1999; Weiler et al., 1996; DeBerry et al., 1997; Ryan et al., 1997; Gotoh et al., 1996). SCF-induced JAK/STAT activation is associated with fetal liver haematopoietic progenitor cells proliferation and differentiation (Linnekin et al., 1996;

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Radosevic et al., 2004). Other studies failed to show JAK/STAT activation after SCF stimulation (100 ng/ml), in MO7e and HCD57 cells, but reasons for this difference remain unclear (Gotoh et al., 1996; Jacobs-Helber et al., 1997). 6.6. Downregulation of c-Kit signalling The protein kinase C (PKC) also interacts with c-Kit, and phosphorylates on S741 and S746 of the kinase insert. These phosphorylations lead to inhibition of the c-Kit kinase activity (Blume-Jensen et al., 1994, 1995). PKC also mediates downregulation of c-Kit by activating a pathway leading to shedding of the extracellular domain of c-Kit (Yee et al., 1993, 1994a). The protein phosphatase SHP-1 (SH2 domaincontaining tyrosine phosphatase-1) negatively regulates c-Kit signalling through binding to the phosphorylated Y570 in the juxtamembrane domain (Kozlowski et al., 1998). The suppressors of cytokine signalling (SOCS)-1 and 6 also downregulate c-Kit signalling. SOCS-1 binds Grb2 (Growth factor Receptor-Bound protein 2) and the protein vav (human vaccinia virus oncogene homolog), leading to inhibition of SCF-induced proliferation (De Sepulveda et al., 1999). SOCS-6 interacts with the phosphorylated Y568 in the juxtamembrane domain of c-Kit. This leads to downregulation of SCF-induced p38 and ERK1/2 phosphorylations, and proliferation (Bayle et al., 2004). Cbl (Casitas B-lineage) family members are newly established as components of the ubiquitin ligation machinery involved in the degradation of phosphorylated proteins. Upon SCF stimulation, recruitment of Src kinases or maybe other proteins to phosphorylated Y568/Y570 leads to recruitment of Cbl proteins (Zeng et al., 2005). Once phosphorylated, Cbl proteins mediate c-Kit ubiquitination and degradation through the proteasome and/or lysosome pathways, leading to c-Kit downregulation (Zeng et al., 2005). 6.7. SCF-induced c-Kit internalization Internalization of the receptor may be a mechanism to attenuate cellular response to SCF. c-Kit is rapidly internalized after SCF binding (Yee et al., 1993, 1994a; Gommerman et al., 1997; Miyazawa et al., 1994). c-Kit internalization requires kinase activity, PI3-kinase activation and Ca2+ influx (Yee et al., 1993). But mutation of c-Kit on Y721 in the PI3-kinase binding site does not impair c-Kit internalization (Yee et al., 1993, 1994a). The kinetic of SCF-induced c-Kit internalization was studied in NIH3T3 fibroblasts transfected to express either the GNNK+ or GNNK− isoforms. The GNNK− isoform shows faster SCF-induced internalization than the GNNK+ isoform (Caruana et al., 1999). Since the GNNK− isoform of c-Kit shows stronger and more rapid activation of Src family kinases than the GNNK+ isoform (Voytyuk et al., 2003), a role for Src kinases in SCF-induced c-Kit internalization has been proposed. The PP1 inhibitor of Src family kinases blocks SCF-induced cKit internalization (Broudy et al., 1999). This result was confirmed by analysing c-Kit internalization using a functional c-Kit-EGFP chimera (c-Kit linked to an enhanced green

fluorescent protein), where internalization was shown to be Src-, but not PI3-kinase-dependent (Jahn et al., 2002). These authors suggest an interesting hypothesis that c-kit is present on lipid rafts, and that the integrity of functional rafts may be a prerequisite for internalization of c-Kit following SCF stimulation (Jahn et al., 2002). 7. Effect of SCF on inflammatory cells Both mast cells and eosinophils express SCF (Hartman et al., 2001; de Paulis et al., 1999a; Zhang et al., 1998) and its c-Kit receptor at the cell membrane (Yarden et al., 1987; Yuan et al., 1997). Because SCF is upregulated in inflammatory conditions both in vitro (Da Silva et al., 2002, 2003, 2004) and in vivo (AlMuhsen et al., 2004; Huttunen et al., 2002; Otsuka et al., 1998), it may affect inflammatory cell function, and therefore be a potential therapeutic target for inflammatory diseases. 7.1. Mast cells 7.1.1. SCF-induced mast cell development Both W and Sl mice, which have, respectively, mutations on the c-Kit and the SCF (steel) loci are deficient in mast cells (Geissler et al., 1988; Huang et al., 1990; Kitamura and Go, 1979), thus suggesting that the SCF/c-Kit interaction plays a critical role in the development of murine mast cells. Mice homozygous for the viable Sl allele steel-Dickie (Sld) produce sSCF but not mSCF, and show decreased number of mast cells in tissues. This result suggests that the membranebound form of SCF is important for the development of mast cells in vivo (Brannan et al., 1991). In human also, SCF is the main mast cell growth factor, promoting by itself their development from bone marrow, cord blood, or peripheral blood progenitor cells in vitro (Kirshenbaum et al., 1992; Valent et al., 1992; Rottem et al., 1994; Mitsui et al., 1993; Sillaber et al., 1994; Saito et al., 1996). SCF-induced development of mast cells from CD34+ cells is regulated by other co-factors including IL-9 (Matsuzawa et al., 2003), thrombopoietin (Sawai et al., 1999), nerve growth factor (NGF) (Aloe and Levi-Montalcini, 1977), and IL-3 (Kirshenbaum et al., 1992). In the presence of IL-6, cultured SCF-dependent mast cells have a decreased proliferation and expression of c-Kit receptor, together with increased intracellular histamine levels (Kinoshita et al., 1999). Also, SCFinduced mast cell development is shown to be inhibited by GM-CSF (Saito et al., 1996), and by IL-4 (Sillaber et al., 1994). 7.1.2. SCF-induced mast cell survival SCF induces murine mast cells survival via suppression of apoptosis both in vitro (Mekori et al., 1993; Yee et al., 1994b) and in vivo (Finotto et al., 1997; Iemura et al., 1994). The SCF/c-Kit pathway has also been involved in mast cell survival in human (Okayama et al., 1994). First, SCF acts by itself to induce mast cell survival, or in synergism with other growth factors such as IL-3 (Mekori et al., 1993; Gebhardt et al., 2002) or NGF (Kanbe et al., 2000). In addition, increased

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mast cell apoptosis is reported after treatment with the inhibitors of the c-Kit receptor SU4984 and SU5614 (Ma et al., 2000). The transduction pathways involved in the SCF-induced mast cell survival are clearly distinct from those associated with IL-3-mediated effect, as the transcription factor Stat 5 is needed for IL-3 but not SCF-mediated survival (Ikeda et al., 2005). Recently, SCF was shown to promote mast cell survival via inactivation of the Forkhead transcription factor FoxO3a (Forkhead box, class O3A), and MAP ERK kinase (MEK)regulated phosphorylation of the pro-apoptotic protein Bim (Bcl-2 [B-cell lymphoma-2]-interacting modulator of cell death) (Moller et al., 2005). 7.1.3. SCF-induced mast cell chemotaxis SCF is a chemotactic factor for mast cells in vitro (Kiener et al., 2000; Nilsson et al., 1994; Meininger et al., 1992). This has been confirmed by studies in asthmatic patients during the pollen season where the bronchoalveolar lavage fluid presents a chemotactic activity for mast cells, which is partially blocked by an anti-SCF antibody (Olsson et al., 2000). Mast-cell chemotactic activity is also present in the nasal lavage fluid of patients with allergic rhinitis after allergen provocation; it is partially blocked by an anti-SCF antibody (Nilsson et al., 1998). These results are in favor of a chemotactic activity of SCF on mast cells in vivo. The transduction pathways involved in the SCF-induced mast cell migration include activation of the p38 MAP kinase (Jeong et al., 2003; Sundstrom et al., 2001), activation of PI3kinase since genetic or pharmacological inactivation of the p110δ isoform of PI3-kinase in mast cells leads to defective SCF-mediated migration in vitro (Ali et al., 2004), and activation of the Src family kinase Lyn, since Lyn-deficient mast cells show impairment of SCF-induced chemotaxis as compared to wild-type mast cells (O'Laughlin-Bunner et al., 2001). Additionally, the SCF/c-Kit pathway also regulates migration of primary mast cells induced by fibronectin, involving the class IA PI3-kinase and Rac pathways (Tan et al., 2003), or by IgE-allergen in murine bone marrow-derived mast cells, where low doses of SCF (1 ng/ml) enhance, while high doses (from 10 to 100 ng/ml) inhibit this effect in a dosedependent manner (Sawada et al., 2005). These authors suggest that circulating SCF may promote mast cells chemotaxis, while locally produced high doses of SCF may contribute to their accumulation at the site of inflammation. 7.1.4. SCF-induced mast cell adhesion SCF induces bone marrow-derived mast cells adhesion to fibronectin at even lower concentrations (200 pg/ml) as those regulating chemotaxis (Dastych and Metcalfe, 1994; Kinashi and Springer, 1994). Involvement of the c-Kit receptor in SCFinduced mast cell adhesion was demonstrated in mast cells derived from W/W mice, which do not express the extracellular domain of c-Kit, and cannot bind to fibroblasts (Adachi et al., 1992). SCF-induced mast cell adhesion requires c-Kit tyrosine kinase activity, as it is inhibited by the tyrosine kinase inhibitors genistein (Dastych and Metcalfe, 1994) and STI-571 (imatinib

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mesylate, Gleevec®) (Takeuchi et al., 2003). In agreement with this result, mast cells derived from W/Wv mice, which have a missense mutation in the kinase insert of c-Kit, do not adhere to fibronectin upon SCF stimulation (Kinashi and Springer, 1994). Adhesion of mast cell induced by SCF occurs through an integrin receptor, as it is calcium-dependent and can be blocked by an RGD (Arginine–Glycine–aspartic acid)-containing peptide (Dastych and Metcalfe, 1994). Also, the cell surface expression of the adhesion molecule ICAM-1 (Intercellular Adhesion Molecule-1) has been reported to be upregulated by SCF, and synergistically enhanced by TNF-α in the HMC-1 mast cell line, involving the ERK pathway (Tsang et al., 2005). By contrast, other authors failed to show any SCF-induced upregulation of ICAM-1, not of very late antigen VLA-4, macrophage antigen-1 (Mac-1), lymphocyte function-associated antigen-1 (LFA-1), LFA-2, LFA-3 and vascular cell adhesion molecule-1 (VCAM-1) in the HMC-1 mast cell line (Wedi et al., 1996). Upregulation of another fibronectin receptor, VLA-5, has been reported for SCF shortly after treatment, which was inhibited by an anti-VLA-5 antibody, therefore involving SCF in mast cell adhesion to fibronectin (Kinashi and Springer, 1994). Transduction mechanisms involve PLC-γ and PI3-kinase activation for SCF-induced cell-matrix adhesion (Kinashi and Springer, 1994; Kinashi et al., 1995), inhibited by wortmanin and apigenin, thus confirming implication of PI3-kinase and involving the MAP kinases pathway, respectively (Lorentz et al., 2002). 7.1.5. SCF-induced mast cell activation SCF by itself stimulates mast cell degranulation (Columbo et al., 1992; Takaishi et al., 1994; Taylor et al., 1996a,b). Cordblood-derived human mast cells produce IL-13 in the presence of SCF (Kanbe et al., 1999). SCF can also induce the release of IL-6 from murine mast cells in vitro (Gagari et al., 1997). Small amounts of TNF-α and IL-4 are released in response to SCF stimulation (Gibbs et al., 1997; Okayama et al., 1995). In addition, decreased IL-4 production is observed in SCFdeficient mice as compared to controls during local inflammation (Fantuzzi and Dinarello, 1998). SCF can also potentiate mast cell degranulation during IgEdependent activation and release of histamine and arachidonic acid metabolites (Coleman et al., 1993; Nakajima et al., 1992; Bischoff and Dahinden, 1992; Columbo et al., 1992), or serotonin from peritoneal mast cells (Coleman et al., 1993). Also, the IgE-dependent TNF-α, GM-CSF and IL-5 release by mast cells is potentiated by SCF (Okayama et al., 1998). All these reports confirm a role for SCF in mast cell degranulation in tissues. SCF and IgE both together also upregulate the expression of chemokines by mast cells (Oliveira and Lukacs, 2001; Baghestanian et al., 1997). SCF promotes expression and release of CCL2 (monocyte chemotactic protein MCP-1) by human lung mast cells (Baghestanian et al., 1997), as well as of CCL22 (macrophage-derived chemokine MDC) and CCL17 (thymus and activation regulated chemokine TARC) (Oliveira and Lukacs, 2001). SCF and IgE upregulate also the expression

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of the chemokine receptors CCR1, CCR2, CCR3 and CCR5 at the mast cell membrane (Oliveira and Lukacs, 2001), therefore confirming activation of the mast cell by SCF in the IgEdependent process. 7.2. Eosinophils First, human peripheral blood eosinophils express and release SCF (Hartman et al., 2001), as well as express its cKit receptor at their cell surface (Yuan et al., 1997). Similarly, cKit expression is reported in murine eosinophils (Oliveira et al., 2002). Direct and indirect effects of SCF on the eosinophils have been reported. Direct effects of SCF on eosinophils include development of eosinophils by murine marrow cells, an effect which is enhanced by granulocyte colony stimulating factor G-CSF (Metcalf et al., 2002). SCF also induces adhesion of eosinophils to fibronectin and to vascular cell adhesion molecule VCAM-1 in vitro, an effect which is totally inhibited by anti-α4 and antiβ1 integrin antibodies, therefore dependent on very late antigen VLA-4 (α4β1) (Yuan et al., 1997). In addition, SCF induces murine eosinophils to degranulate and release eosinophil peroxidase (EPO) and leukotriene C4 (LTC4) in a dosedependent manner (Oliveira et al., 2002). SCF also induces eosinophils to produce CC chemokines, including RANTES (regulated on activation, normal T expressed and secreted), macrophage-derived chemokine (MDC), macrophage inflammatory protein-1β (MIP-1β), and CCL6 (C10) (Oliveira et al., 2002). In the same study, a gene array analysis reveals that more than 150 genes related to inflammation are up-regulated in eosinophils following SCF stimulation (Oliveira et al., 2002). In addition, indirect effect of SCF on the eosinophil is reported. SCF produces the leukotriene B4 (LTB4) in the airways in a murine model of allergic inflammatory response. In turn, LTB4 augmentation leads to recruitment of eosinophils at the site of inflammation (Klein et al., 2000, 2001). 8. The SCF/c-kit complex as a target for inflammatory diseases 8.1. Skin inflammation In mice, the subcutaneous injection of recombinant SCF induces a significant expansion of tissue mast cells population. Cessation of SCF treatment is associated with a decrease in mast cells number, which is related with the apoptosis of large number of cutaneous mast cells. This is consistent with the finding that SCF induces mast cell survival via inhibition of their apoptosis (Iemura et al., 1994; Tsai et al., 1991; Maurer and Galli, 2004). In human, the effect of a daily subcutaneous injection of rhSCF (5–50 μg/kg/day) over 2 weeks was studied in a phase I clinical trial including 10 patients with advanced breast carcinoma. All biopsies performed at rhSCF-injected sites exhibited anaphylactic degranulation of both mature and immature mast cells, an acute inflammatory response characterized by the migration of neutrophils, basophils (some of

which exhibited evidence of degranulation) and eosinophils. By contrast, the biopsies performed at sites distant from those injected with rhSCF contained no evidence of mast cell degranulation or acute inflammation (Costa et al., 1996; Dvorak et al., 1998). Huttunen and collaborators studied the expression of SCF and c-Kit in skin biopsies of patients during wound healing, chronic wound or psoriasis (Huttunen et al., 2002). In chronic wound as well as in psoriasis, both SCF and c-Kit are intensely expressed, that leads to persistent mast cell growth and activation. In wound healing, where only temporary mast cell activation seems to be needed, SCF levels increase rapidly in the early stages of healing, and declines thereafter, paralleling a transient mast cell activation (Huttunen et al., 2002). Recently, mast cell accumulation and increased levels of SCF were found in a murine model of scleroderma, suggesting that locally produced SCF may influence mast cell recruitment in this disease (Wang et al., 2005). 8.2. Rheumatoid arthritis Mast cells may play a role in the pathogenesis of rheumatoid arthritis (Lee et al., 2002; Woolley, 2003). Indeed, increased numbers of mast cells have been found in the human rheumatoid synovium, and their number correlates with the activity of the disease (Gotis-Graham and McNeil, 1997). These mast cells stain positively to TNF-α-immunolabelling (Juurikivi et al., 2005). Additionally, inhibition of c-Kit by its inhibitor STI-571 leads to significant reduction of TNF-α production in synovial tissue cultures, as well as apoptosis in cultured mast cells (Juurikivi et al., 2005), which is probably a key mechanism of the efficient rheumatoid arthritis treatment with anti-TNF-α (for review, see Haraoui, 2005). 8.3. Allergic rhinitis Allergic rhinitis is associated with an increase in mast cell number in the nasal epithelium during seasonal allergen exposure (Otsuka et al., 1998; Nouri-Aria et al., 2005). In patients with seasonal allergic rhinitis, the number of nasal ciliated epithelial cells expressing SCF is greater than in control subjects (Kim et al., 1997). This increase is associated with increased levels of SCF (Otsuka et al., 1998), which can be reverted by in vivo topical corticosteroid treatment (Kim et al., 1997). The function of SCF in nasal lavage fluid of patients with allergic rhinitis after allergen provocation has been studied as for its mast cell chemotactic activity, showing it is partially blocked by an anti-SCF blocking antibody (Nilsson et al., 1998). 8.4. Asthma Recently, significant increases in SCF and c-Kit mRNA were found in the epithelium and subepithelium of asthmatic patients compared with controls (Al-Muhsen et al., 2004; Da Silva et al., 2006). In the same study, the authors also found significant differences in the number of SCF and c-Kit expressing cells by in situ hybridization and immunohistochemistry, suggesting an

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important role for SCF in the pathophysiology of asthma. Lukacs and collaborators studied the role of SCF in a murine model of allergic eosinophilic airways inflammation (Lukacs et al., 1996). Increased SCF protein production occurs 8 h after the challenge in both lungs and serum of allergen-challenged, but not vehicle-challenged, mice. This result was confirmed by Campbell and collaborators, in the same model of allergic asthma (Campbell et al., 1999). The authors also found decreased allergen-induced airway hyperresponsiveness and eosinophil infiltration in SCF-deficient mice, compared to control mice. Furthermore, intratracheal instillation of recombinant SCF induces airway hyperresponsiveness in control, unsensitized mice, but not in mast cell-deficient mice. This result suggests that SCF-induced airway hyperresponsiveness is dependent on mast cell activation (Campbell et al., 1999). The implication of SCF in mast cell recruitment in asthma was confirmed in human by Olsson and collaborators (Olsson et al., 2000). They showed that mast cell chemotactic activity of bronchoalveolar lavage fluid, collected from asthmatic patients during the pollen season, was partially blocked by an anti-SCF antibody (Olsson et al., 2000). The potential of mast cell development related to SCF was studied on peripheral blood CD34+ cells, generating significantly more mast cells at 6 weeks of culture upon stimulation with SCF alone or SCF+ thrombopoietin in asthmatic patients than healthy controls (Mwamtemi et al., 2001). Since the SCF/c-Kit pathway is involved in the recruitment of mast cells and eosinophils in asthma, downregulation of SCF expression or inhibition of c-Kit activation may lead to decreased airway inflammation. Corticosteroid treatment is highly effective in patients with allergic asthma, and leads to a marked decrease in mast cell numbers. This effect may be due, at least partially, to downregulation of SCF expression, as glucocorticoids reduce its production both in vitro (Da Silva et al., 2002; Kassel et al., 1998; Finotto et al., 1997) and in vivo (Finotto et al., 1997; Da Silva et al., 2006). Consistent with this finding, intranasal administration of SCF antisense oligonucleotides decreases lung SCF protein expression in a murine model of asthma, as well as airway hyperresponsiveness, IL-4 production and eosinophil number in the bronchoalveolar lavage (Finotto et al., 2001). In addition, inhibition of SCF with an anti-SCF blocking antibody also leads to significant decrease of histamine levels and eosinophil infiltration in a murine model of allergic asthma (Lukacs et al., 1996). Altogether, these findings argue in favor of a role for SCF in the eosinophilic and mast cell infiltration in the airways in asthma. 9. Conclusion Taken together, the data presented provide evidence that the SCF/c-Kit complex plays a central role in inflammation, and may therefore be a potential therapeutic target in inflammatory diseases. The discovery of more selective c-Kit inhibitors or antagonists will provide novel approaches for the downregulation of mast cell and eosinophil numbers in inflammatory conditions.

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