Abstract
Proteinase 3 (PR3) is a 29-kDa serine proteinase, with homology to human leukocyte elastase (HLE) and cathepsin G (Cat G), secreted from activated neutrophils. It was found that PR3, but not HLE and Cat G, activated the oral epithelial cells to produce interleukin (IL)-8 and monocyte chemoattractant protein (MCP)-1 and to express intracellular adhesion molecule (ICAM)-1. Oral epithelial cells express protease-activated receptor (PAR)-1, -2, and -3 mRNA, and the expression of PAR-2 on the cell surface was promoted by PR3. PR3 cleaved the peptide corresponding to the N terminus of PAR-2 with exposure of its tethered ligand. The production of cytokine induced by PR3 was completely abolished by a phospholipase C inhibitor. These findings suggested that PR3 but not HLE and Cat G activated oral epithelial cells through G protein-coupled PAR-2. In human gingival fibroblasts (HGF), HLE and Cat G as well as PR3 were active to produce IL-8 and MCP-1. Human oral epithelial cells but not HGF express mRNA and protein of secretory leukocyte protease inhibitor (SLPI), an inhibitor of HLE and Cat G, and recombinant SLPI clearly inhibited the activation of HGF induced by HLE and Cat G but not by PR3. HLE and Cat G cleaved the peptide corresponding to the N terminus of PAR-2 with exposure of its tethered ligand, as well as PR3. These results suggest that neutrophil serine proteinases have equal ability to activate human nonepithelial cells through PAR-2 to produce inflammatory cytokines.
