ReviewStem cell factor and its receptor c-Kit as targets for 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.
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