Intracystic fluid pressure is thought to be involved in odontogenic cyst growth. In this study, we investigated the effects of positive pressure on the expression of interleukin-1 alpha (IL-1 alpha), matrix metalloproteinases ( MMPs), and prostaglandin E-2(PGE(2)) in odontogenic keratocysts to determine whether this pressure stimulates inflammatory cytokine production and signaling of osteoclastogenic events. Positive pressure enhanced the expression of IL-1 alpha mRNA and protein in odontogenic keratocyst epithelial cells, and increased the secretion of MMP-1, MMP-2, MMP-3, and PGE2 in a co-culture of odontogenic keratocyst fibroblasts and the epithelial cells. The pressure-induced secretions were inhibited by an interleukin-1 receptor antagonist. Recombinant human interleukin-1 alpha ( rhIL-1 alpha) increased the secretion of MMP-1, MMP-2, MMP-3, and PGE(2) in the fibroblasts. Furthermore, in the fibroblasts, rhIL-1 alpha enhanced the expression of macrophage colony-stimulating factor (M-CSF) mRNA, and rhIL-1 alpha- induced PGE(2) increased the expression of nuclear factor kappa B ligand (RANKL) mRNA. Thus, positive pressure may play a crucial role in odontogenic keratocyst growth via stimulating the expression of IL-1 alpha in epithelial cells.