Interleukin-1β-Induced Promatrilysin Expression is Mediated by NFκB-Regulated Synthesis of Interleukin-6 in the Prostate Carcinoma Cell Line, LNCaP1

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