Roles of IL-1α in the Growth of Keratocystic Odontogenic Tumor / Oral Science International

ABSTRACT

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)-1α and demonstrated the biochemical mechanisms of the tumor growth. We found that IL-1α is strongly expressed in the lining epithelial cells of the tumors, and the intracystic fluid levels of IL-1α are significantly higher than the levels of the other inflammatory cytokines of IL-6 and tumor necrosis factor-α (TNF-α). The expression of IL-1α in the epithelial cells decreases after the marsupialization of the tumor. <i>In vitro</i> experiments also reveal that positive pressure enhances the expression of IL-1α in the tumor epithelial cells in culture. IL-1α 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, IL-1α increases the expression of proMMP-1, proMMP-2, and proMMP-3. IL-1α also activates proMMP-2 by inducing the expression of membrane-type 1 matrix metalloproteinase (MT1-MMP) synergistically with type I collagen. Furthermore, IL-1α increases the expression of macrophage colony-stimulating factor (M-CSF) and cyclooxygenase (COX)-2 in the fibroblasts. The COX-2 synthesizes prostaglandin E₂ (PGE₂), and the secreted PGE₂ stimulates the expression of receptor activator of nuclear factor-κB ligand (RANKL), while neither IL-1α nor PGE₂ affects the expression of osteoprotegerin (OPG) 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-1α expression in epithelial cells, and the released IL-1α may play a crucial role in the growth of keratocystic odontogenic tumors by stimulating proteolytic enzyme production and osteoclastogenesis.