Roles of IL-1 alpha in the Growth of Keratocystic Odontogenic Tumor

Keratocystic odontogenic tumors have a high level of proliferative activity in epithelial cells and they tend to grow aggressively in the jaw. The tumor dramatically decreases in size by decompression of the intracystic fluid pressure. We herein focused on the roles of interleukin (IL)-1 alpha and demonstrated the biochemical mechanisms of the tumor growth. We found that 1L-1 alpha is strongly expressed in the lining epithelial cells of the tumors, and the intracystic fluid levels of 1L-l alpha are significantly higher than the levels of the other inflammatory cytokines of IL-6 and tumor necrosis factor-alpha (TNF-alpha). The expression of 1L-l alpha in the epithelial cells decreases after the marsupialization of the tumor. In vitro experiments also reveal that positive pressure enhances the expression of IL-1 alpha in the tumor epithelial cells in culture. IL-l alpha stimulates the production of matrix metalloproteinase (MMP)-9, and activates the released proMMP-9 by increasing the expression of proMMP-3 and plasminogen activator urokinase (u-PA) in the tumor epithelial cells. In the fibroblasts isolated from the tumors, 1L-l alpha increases the expression of proMMP-1, proMMP-2, and proMMP-3. IL-l alpha also activates proMMP-2 by inducing the expression of membrane-type 1 matrix metalloproteinase (MT1-MMP) synergistically with type I collagen. Furthermore, IL-l alpha increases the expression of macrophage colony-stimulating factor (M-CSF) and cyclooxygenase (COX)-2 in the fibroblasts. The COX-2 synthesizes prostaglandin E-2 (PG E2), and the secreted PG E-2 stimulates the expression of receptor activator of nuclear factor-KB ligand (RANKL), while neither 1L-l alpha nor PG E-2 affects the expression of osteoprotegerin (OPC) in the fibroblasts. The fibroblasts express Ca2+-sensing receptor (CasR) on the cell surface, and extracellular Ca2+ activates COX-2 expression via the CasR. A strong relationship may thus be present between the intracystic fluid pressure and IL-l alpha expression in epithelial cells, and the released IL-l alpha may play a crucial role in the growth of keratocystic odontogenic tumors by stimulating proteolytic enzyme production and osteoclastogenesis.