RESUMEN

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

Asunto(s)

Adenocarcinoma/patología , Precursores Enzimáticos/biosíntesis , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Interleucina-1/farmacología , Interleucina-6/fisiología , Metaloendopeptidasas/biosíntesis , FN-kappa B/fisiología , Proteínas de Neoplasias/biosíntesis , Neoplasias de la Próstata/patología , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Cicloheximida/farmacología , Proteínas de Unión al ADN/fisiología , Inducción Enzimática/efectos de los fármacos , Precursores Enzimáticos/genética , Humanos , Interleucina-6/biosíntesis , Interleucina-6/genética , Interleucina-6/farmacología , Masculino , Metaloendopeptidasas/genética , FN-kappa B/antagonistas & inhibidores , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/genética , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Inhibidores de la Síntesis de la Proteína/farmacología , Pirrolidinas/farmacología , ARN Mensajero/biosíntesis , ARN Mensajero/genética , ARN Neoplásico/biosíntesis , ARN Neoplásico/genética , Factor de Transcripción STAT3 , Transducción de Señal/fisiología , Sulfasalazina/farmacología , Tiocarbamatos/farmacología , Transactivadores/fisiología , Activación Transcripcional/efectos de los fármacos , Células Tumorales Cultivadas/efectos de los fármacos , Células Tumorales Cultivadas/metabolismo