SummaryStem cell factor (SCF), also known as mast cell growth factor, kit ligand, and Steel factor, is the ligand for the tyrosine kinase receptor (SCFtL) that is encoded by the c-kit proto-oncogene. We analyzed the effects of recombinant human SCF (r-hSCF, 5-50 btg/kg/day, injected subcutaneously) on mast cells and melanocytes in a phase I study of 10 patients with advanced breast carcinoma. A wheal and flare reaction developed at each r-hSCF injection site; by electron microscopy, most dermal mast cells at these sites exhibited extensive, anaphylactic-type degranulation. A 14-d course ofr-hSCF significantly increased dermal mast cell density at sites distant to those injected with the cytokine and also increased both urinary levels of the major histamine metabolite, methyl-histamine, and serum levels of mast cell 0rFive subjects developed areas of persistent hyperpigmentation at r-hSCF injection sites; by light microscopy, these sites exhibited markedly increased epidermal melanization and increased numbers of melanocytes. The demonstration that r-hSCF can promote both the hyperplasia and the functional activation of human mast cells and melanocytes in vivo has implications for our understanding of the role of endogenous SCF in health and disease. These findings also indicate that the interaction between SCF and its receptor represents a potential therapeutic target for regulating the numbers and functional activity of both mast cells and cutaneous melanocytes.
Stem cell factor (SCF), the ligand for the receptor (SCFR) that is encoded by the c-kit proto-oncogene, has many important effects in mouse and human mast cell development, survival, and function. SCF can promote mast cell survival by suppressing apoptosis, induce mast cell hyperplasia in murine rodents, experimental primates and humans, directly induce SCFR-dependent mast cell mediator release, and significantly modulate the extent of mast cell activation by FcεRI-dependent mechanisms. These findings raise several clinical issues and, in some cases, point to potentially significant therapeutic opportunities.
By in situ hybridization, 44-100% of the blood eosinophils from five patients with hypereosinophilia and four normal subjects exhibited intense hybridization signals for TNF-a mRNA. TNF-a protein was detectable by immunohistochemistry in blood eosinophils of hypereosinophilic subjects, and purified blood eosinophils from three atopic donors exhibited cycloheximide-inhibitable spontaneous release of TNF-a in vitro. Many blood eosinophils (39-91%) from hypereosinophilic donors exhibited intense labeling for macrophage inflammatory proteinla (MIP-la) mRNA, whereas eosinophils of normal donors demonstrated only weak or undetectable hybridization signals for MIP-la mRNA. Most tissue eosinophils infiltrating nasal polyps were strongly positive for both TNF-a and MIP-la mRNA. By Northern blot analysis, highly enriched blood eosinophils from a patient with the idiopathic hypereosinophilic syndrome exhibited differential expression of TNF-a and MIP-la mRNA. These findings indicate that human eosinophils represent a potential source of TNF-a and MIP-la, that levels of expression of mRNA for both cytokines are high in the blood eosinophils of hypereosinophilic donors and in eosinophils infiltrating nasal polyps, that the eosinophils of normal subjects express higher levels of TNF-a than MIP-la mRNA, and that eosinophils purified from the blood of atopic donors can release TNF-a in vitro. (J. Clin. Invest. 1993. 91:2673-2684
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