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

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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.

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.

Section snippets

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, Da Silva et al., 2002), bronchial smooth muscle cells (Kassel et al., 1999), endothelial cells (Heinrich et al., 1993),

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, 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

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

Regulation of SCF and c-Kit production

SCF promoter activity is increased by cyclic AMP (cAMP) (Taylor et al., 1996a, Taylor et al., 1996b, 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

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. 2, Fig. 3).

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, Da Silva et al., 2003, Da Silva et al., 2004) and in vivo (Al-Muhsen et al., 2004, Huttunen et al., 2002, Otsuka et al., 1998), it may affect inflammatory cell function, and therefore be a potential

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

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.

References (196)

  • V.C. Broudy et al.

    Analysis of c-kit receptor dimerization by fluorescence resonance energy transfer

    Blood

    (1998)
  • V.C. Broudy et al.

    Signaling via Src family kinases is required for normal internalization of the receptor c-Kit

    Blood

    (1999)
  • V.C. Broudy et al.

    The fifth immunoglobulin-like domain of the Kit receptor is required for proteolytic cleavage from the cell surface

    Cytokine

    (2001)
  • E. Campbell et al.

    Stem cell factor-induced airway hyperreactivity in allergic and normal mice

    Am. J. Pathol.

    (1999)
  • V. Chesneau et al.

    Catalytic properties of ADAM19

    J. Biol. Chem.

    (2003)
  • P.S. Crosier et al.

    Expression of isoforms of the human receptor tyrosine kinase c-kit in leukemic cell lines and acute myeloid leukaemia

    Blood

    (1993)
  • A.C. Cruz et al.

    Tumor necrosis factor-α-converting enzyme controls surface expression of c-kit and survival of embryonic stem cell-derived mast cells

    J. Biol. Cell.

    (2004)
  • A.M. Dvorak et al.

    Ultrastructural analysis of human skin biopsy specimens from patients receiving recombinant human stem cell factor: subcutaneous injection of rhSCF induces dermal mast cell degranulation and granulocyte recruitment at the injection site

    J. Allergy Clin. Immunol.

    (1998)
  • S. Finotto et al.

    Local administration of antisense phosphorothioate oligonucleotides to the c-kit ligand, stem cell factor, suppresses airway inflammation and IL-4 production in a murine model of asthma

    J. Allergy Clin. Immunol.

    (2001)
  • J.G. Flanagan et al.

    Transmembrane form of the kit ligand growth factor is determined by alternative splicing and is missing in the Sld mutant

    Cell

    (1991)
  • E. Gagari et al.

    Differential release of mast cell interleukin-6 via c-kit

    Blood

    (1997)
  • S. Gallea-Robache et al.

    A metalloproteinase inhibitor blocks the shedding of soluble cytokine receptors and processing of transmembrane cytokine precursors in human monocytic cells

    Cytokine

    (1997)
  • E.N. Geissler et al.

    The dominant-white spotting (W) locus of the mouse encodes the c-kit proto-oncogene

    Cell

    (1988)
  • B.F. Gibbs et al.

    Human lung mast cells release small amounts of interleukin-4 and tumour necrosis factor-alpha in response to stimulation by anti-IgE and stem cell factor

    Eur. J. Pharmacol.

    (1997)
  • J.L. Gommerman et al.

    Phosphatidylinositol 3-kinase and Ca2+ influx dependence for ligand-stimulated internalization of the c-kit receptor

    J. Biol. Chem.

    (1997)
  • J.L. Gommerman et al.

    Differential stimulation of c-Kit mutants by membrane-bound and soluble Steel Factor correlates with leukemic potential

    Blood

    (2000)
  • A. Gotoh et al.

    Steel factor induces serine phosphorylation of Stat3 in human growth factor-dependent myeloid cell lines

    Blood

    (1996)
  • M. Hartman et al.

    Human peripheral blood eosinophils express stem cell factor

    Blood

    (2001)
  • M.C. Heinrich et al.

    Constitutive expression of steel factor gene by human stromal cells

    Blood

    (1993)
  • B. Heissig et al.

    Recruitement of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand

    Cell

    (2002)
  • R. Herbst et al.

    Substrate phosphorylation specificity of the human c-kit receptor tyrosine kinase

    J. Biol. Chem.

    (1991)
  • S.T. Hollenbeck et al.

    Stem cell factor and c-kit are expressed by and may affect vascular SMCs through an autocrine pathway

    J. Surg. Res.

    (2004)
  • Y.R. Hsu et al.

    The majority of stem cell factor exists as monomer under physiological conditions

    J. Biol. Chem.

    (1997)
  • E. Huang et al.

    The hematopoietic growth factor KL is encoded by the Sl locus and is the ligand of the c-kit receptor, the gene product of the W locus

    Cell

    (1990)
  • J. Hue et al.

    IL-18 enhances SCF production of melanoma cells by regulating ROI and p38 MAPK activity

    Immunol. Lett.

    (2005)
  • S.M. Jacobs-Helber et al.

    Distinct signaling from stem cell factor and erythropoietin in HCD57 cells

    J. Biol. Chem.

    (1997)
  • C. Jiang et al.

    Cloning and characterization of the 5′ flanking region of the stem cell factor gene in rat Sertoli cells

    Gene

    (1997)
  • Y.K. Kim et al.

    Stem cell factor in nasal polyposis and allergic rhinitis: increased expression by structural cells is suppressed by in vivo topical corticosteroids

    J. Allergy Clin. Immunol.

    (1997)
  • T. Kinashi et al.

    Steel factor and c-kit regulate cell-matrix adhesion

    Blood

    (1994)
  • T. Kinashi et al.

    Receptor tyrosine kinase stimulates cell-matrix adhesion by phosphatidylinositol 3 kinase and phospholipase C-gamma 1 pathways

    Blood

    (1995)
  • T. Kinoshita et al.

    Interleukin-6 directly modulates stem cell factor-dependent development of human mast cells derived from CD34(+) cord blood cells

    Blood

    (1999)
  • Y. Kitamura et al.

    Decreased production of mast cells in S1/S1d anemic mice

    Blood

    (1979)
  • A. Konig et al.

    Downregulation of c-kit expression in human endothelial cells by inflammatory stimuli

    Blood

    (1997)
  • K.E. Langley et al.

    Soluble stem cell factor in human serum

    Blood

    (1993)
  • K.E. Langley et al.

    Proprieties of variant forms of human stem cell factor recombinantly expressed in Escherichia coli

    Arch. Biochem. Biophys.

    (1994)
  • K. Ali et al.

    Essential role for the p110delta phosphoinositide 3-kinase in the allergic response

    Nature

    (2004)
  • S.Z. Al-Muhsen et al.

    The expression of stem cell factor and c-kit receptor in human asthmatic airways

    Clin. Exp. Allergy

    (2004)
  • D.M. Anderson et al.

    Alternate splicing of mRNAs encoding human mast cell growth factor and localization of the gene to chromosome 12q22–q24

    Cell Growth Differ.

    (1991)
  • M.T. Aye et al.

    Expression of stem cell factor and c-kit mRNA in cultured endothelial cells, monocytes and cloned human bone marrow stromal cells (CFU-RF)

    Exp. Hematol.

    (1992)
  • S.C. Bischoff et al.

    c-kit ligand: a unique potentiator of mediator release by human lung mast cells

    J. Exp. Med.

    (1992)
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