A fibrogenic cytokine, platelet-derived growth factor (PDGF), enhances mast cell growth indirectly via a SCF- and fibroblast-dependent pathway

Abstract

Mast cell hyperplasia is often observed in dermatoses characterized by fibrosis. Evidence has accumulated showing that a potent fibrogenic cytokine, platelet-derived growth factor (PDGF), plays a pathogenic role in dermal fibrosis. To clarify the mechanism of mast cell hyperplasia associated with fibrosis, we investigated the effect of PDGF on mast cell proliferation and the expression of stem cell factor (SCF), a potent growth factor for mast cells, in fibroblasts. When mouse bone marrow-derived mast cells (BMMC) were cultured on a NIH/3T3 fibroblast monolayer, mast cell proliferation was stimulated in both cell number and total histamine content by all isoforms of PDGF (-AA, -AB, and -BB); however, none of the isoforms had any effect on [3H] thymidine incorporation in BMMC in the absence of fibroblasts. The effect of PDGF-AB and -BB were abrogated either by the addition of anti- PDGF-AB antibody or by the separation of mast cells and fibroblasts by a permeable membrane filter with a pore size of 0.2 μm. Immunoblotting of the NIH/3T3 fibroblasts treated with PDGF revealed an enhanced expression of SCF in the membrane fraction and the effect of PDGF was neutralized by the addition of antibody against SCF. Moreover, no effect of PDGF was observed when BMMC were prepared from W/W(v) mice that lack functional c-kit as the SCF receptor or when 3T3 fibroblasts were prepared from Sl/Sl(d) mice that lack membrane-bound SCF. These results suggest that the fibrogenic cytokine PDGF stimulates mast cell hyperplasia via the expression of membrane-bound SCF by fibroblasts in association with fibrosis of the skin.