Interleukin-1 beta-induced promatrilysin expression is mediated by NF kappa B-regulated synthesis of interleukin-6 in the prostate carcinoma cell line, LNCaP

Previously, our laboratory showed that interleukin-1 beta (IL-1 beta) secre ted by lipopolysaccharide-activated monocytes induces promatrilysin express ion in the prostate carcinoma cell line, LNCaP. We now demonstrate that IL- 1 beta -induced promatrilysin expression is mediated by an indirect mechani sm that requires nuclear factor Kappa B (NF kappaB)- dependent synthesis of IL-6. Inhibition of protein synthesis with cyclohexamide blocked IL-1 beta -mediated induction of matrilysin mRNA suggesting that synthesis of one or more additional factors is required for IL-1 beta -induced promatrilysin p rotein expression. Blockage of NF kappaB transactivation activity abrogated IL-1 beta -induced promatrilysin expression to baseline levels suggesting that NF kappaB transactivation activity is necessary. Inhibition of IL-6 ac tivity attenuated IL-1 beta -induced promatrilysin, but not NF kappaB trans activation activity indicating that IL-6 acts downstream of NF kappaB in po tentiation of IL-1 beta -mediated promatrilysin expression. Inhibition of p rotein synthesis with cyclohexamide did not alter IL-6-induced induction of matrilysin mRNA indicating that, contrary to the mechanism by which IL-1 b eta regulates promatrilysin expression, IL-6-mediated matrilysin mRNA expre ssion does not require new protein synthesis. Transient transfection with d ominant negative STAT3 inhibited IL-1 beta- and IL-6-induced promatrilysin. These data provide evidence that NF kappaB-mediated IL-6 synthesis is requ ired for IL-1 beta -induced promatrilysin expression, and IL-6 signaling th rough STAT3 plays a role in IL-1 beta -induced promatrilysin expression.