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 becaus e of their increased number in chronic inflammatory reactions. In a pr evious study, we had shown that human mast cells readily attach and fo rm heterotypic cell-cell contacts when seeded on top of fibroblast mon olayers. Here, we report that human mast cells stimulate fibroblast pr oliferation after cell-cell contact. Proliferation was measured by 5-b romo-2'-deoxyuridine or [H-3]thymidine uptake of subconfluent fibrobla st monolayers after attachment of mast cells that had been preincubate d with mitomycin C. An 18-h coculture of the human mast cell line HMC- 1 doubled proliferation of normal skin fibroblasts. Moreover, normal m ast cells prepared from neonatal foreskin doubled fibroblast prolifera tion. The stimulatory effect was dependent on heterotypic cell-cell co ntact since it was not transferred by tissue culture supernatants from mast cells, We hypothesized that mast cell cytokines secreted after h eterotypic cell-cell contact stimulate fibroblast proliferation. Sever al mast cell-derived cytokines were tested for effects on fibroblast p roliferation, Only IL-4 was able to double fibroblast proliferation. A dditional 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 fibrob lasts since it amplifies the action of low doses of obligatory fibrobl ast growth factors such as fibroblast growth factor or platelet-derive d growth factor.