Human mast cells augment fibroblast proliferation by heterotypic cell-cell adhesion and action of IL-4

Mast cells have been implicated in the pathogenesis of fibrosis because of their increased number in chronic inflammatory reactions. In a previous study, we had shown that human mast cells readily attach and form heterotypic cell-cell contacts when seeded on top of fibroblast monolayers. Here, we report that human mast cells stimulate fibroblast proliferation after cell-cell contact. Proliferation was measured by 5-bromo-2'-deoxyuridine or [3H]thymidine uptake of subconfluent fibroblast monolayers after attachment of mast cells that had been preincubated with mitomycin C. An 18-h coculture of the human mast cell line HMC-1 doubled proliferation of normal skin fibroblasts. Moreover, normal mast cells prepared from neonatal foreskin doubled fibroblast proliferation. The stimulatory effect was dependent on heterotypic cell-cell contact since it was not transferred by tissue culture supernatants from mast cells. We hypothesized that mast cell cytokines secreted after heterotypic cell-cell contact stimulate fibroblast proliferation. Several mast cell-derived cytokines were tested for effects on fibroblast proliferation. Only IL-4 was able to double fibroblast proliferation. Additional experiments revealed that: 1) the stimulatory effect of IL-4 as well as of the mast cell coculture could be completely abrogated by preincubation of fibroblasts with an anti-IL-4R mAb blocking ligand binding; 2) mast cell-derived IL-4 acts as a second signal for fibroblasts since it amplifies the action of low doses of obligatory fibroblast growth factors such as fibroblast growth factor or platelet-derived growth factor.