Mast cell expression of gelatinases A and B is regulated by kit ligand andTGF-beta

Our prior work shows that cultured BR cells derived from dog mastocytomas s ecrete the 92-kDa proenzyme form of gelatinase B. We provided a possible li nk between mast cell activation and metalloproteinase-mediated matrix degra dation by demonstrating that alpha-chymase, a serine protease released from secretory granules by degranulating mast cells, concerts progelatinase B t o an enzymatically active form. The current work; shows that these cells al so secrete gelatinase II. Furthermore, gelatinases A and B both colocalize to alpha-chymase-expressing cells of canine airway, suggesting that normal mast cells are a source of gelatinases in the lung. In BR cells, gelatinase B and alpha-chymase expression are regulated? whereas gelatinase A express ion is constitutive. Progelatinase B mRNA and enzyme expression are strongl y induced by the critical mast cell growth factor, kit ligand, which is pro duced by fibroblasts and other stromal tells. Induction of progelatinase B is blocked hi. U-73122, Ro31-8220, and thapsigargin, implicating phospholip ase C, protein kinase C. and Ca2+, respectively, in the kit Ligand effect, The profibrotic cytokine TGF-beta virtually abolishes the gelatinase B mRNA signal and also attenuates kit ligand-mediated induction of gelatinase B e xpression. suggesting that an excess of TGF-beta in inflamed or injured tis sues may alter mast cell expression of gelatinase BI which is implicated in extracellular matrix degradation, angiogenesis, and apoptosis In summary, these data provide the first evidence that normal mast cells express gelati nases A and B and suggest pathways by which their regulated expression by m ast tells can influence matrix remodeling and fibrosis.