PROMOTION OF MOUSE FIBROBLAST COLLAGEN GENE-EXPRESSION BY MAST-CELLS STIMULATED VIA THE FC(EPSILON)RI - ROLE FOR MAST CELL-DERIVED TRANSFORMING GROWTH-FACTOR-BETA AND TUMOR-NECROSIS-FACTOR-ALPHA

Chronic allergic diseases and other disorders associated with mast cel l activation can also be associated with tissue fibrosis, but a direct link between mast cell mediator release and fibroblast collagen gene expression has not been established. Using in situ hybridization, we s how that the elicitation of an IgE-dependent passive cutaneous anaphyl axis (PCA) reaction in mice results in a transient, but marked augment ation of steady state levels of type alpha-1 (I) collagen mRNA in the dermis. While peak levels of collagen mRNA expression in the skin are observed 16-24 h after mast cell activation, substantial numbers of de rmal cells are strongly positive for collagen mRNA at 1 and 2 h after antigen challenge, before circulating inflammatory cells are recruited into the tissues. Furthermore, experiments in mast cell-reconstituted or genetically mast cell-deficient WBB6F(1)-W/W(n)u mice demonstrate that the increased expression of collagen mRNA at sites of PCA reactio ns is entirely mast cell dependent. In vitro studies show that the sup ernatants of mouse serosal mast cells activated via the Fc epsilon RI markedly increase type alpha-1 (I) collagen mRNA levels in mouse embry onic skin fibroblasts, and also upregulate collagen secretion by these cells. The ability of mast cell supernatants to induce increased stea dy state levels of collagen mRNA in mouse skin fibroblasts is markedly diminished by absorption with antibodies specific for either of two m ast cell-derived cytokines, transforming growth factor beta (TGF-beta 1) or tumor necrosis factor alpha (TNF-alpha), and is eliminated entir ely by absorption with antibodies against both cytokines. Taken togeth er, these findings demonstrate that IgE-dependent mouse mast cell acti vation can induce a transient and marked increase in steady state leve ls of type alpha-1 (I) collagen mRNA in dermal fibroblasts and that ma st cell-derived TGF-beta 1 and TNF-alpha importantly contribute to thi s effect.