Previously, our laboratory showed that interleukin-1β (IL-1β) secreted by lipopolysaccharide-activated monocytes induces promatrilysin expression in the prostate carcinoma cell line, LNCaP. We now demonstrate that IL-1β-induced promatrilysin expression is mediated by an indirect mechanism that requires nuclear factor Kappa B (NFκB) -dependent synthesis of IL-6. Inhibition of protein synthesis with cyclohexamide blocked IL-1β-mediated induction of matrilysin mRNA suggesting that synthesis of one or more additional factors is required for IL-1β-induced promatrilysin protein expression. Blockage of NFκB transactivation activity abrogated IL-1β-induced promatrilysin expression to baseline levels suggesting that NFκB transactivation activity is necessary. Inhibition of IL-6 activity attenuated IL-1β-induced promatrilysin, but not NFκB transactivation activity indicating that IL-6 acts downstream of NFκB in potentiation of IL-1β-mediated promatrilysin expression. Inhibition of protein synthesis with cyclohexamide did not alter IL-6-induced induction of matrilysin mRNA indicating that, contrary to the mechanism by which IL1P regulates promatrilysin expression, IL-6-mediated matrilysin mRNA expression does not require new protein synthesis. Transient transfection with dominant negative STAT3 inhibited IL-1β- and IL-6-induced promatrilysin. These data provide evidence that NFκB-mediated IL-6 synthesis is required for IL-1β-induced promatrilysin expression, IL-6 signaling through STAT3 plays a role in IL-1β-induced promatrilysin expression.