title: Interleukin-1beta-induced promatrilysin expression is mediated by NFkappaB-regulated synthesis of interleukin-6 in the prostate carcinoma cell line, LNCaP.
abstract: 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.
authors.affiliation: Department of Radiation Oncology, University of Arizona Health Sciences Center, Tucson, AZ 85724, USA. msuzannestratton@aol.com
authors.forename: M S
authors.initials: MS
authors.lastname: Maliner-Stratton
authors.forename: R D
authors.initials: RD
authors.lastname: Klein
authors.forename: T S
authors.initials: TS
authors.lastname: Udayakumar
authors.forename: R B
authors.initials: RB
authors.lastname: Nagle
authors.forename: G T
authors.initials: GT
authors.lastname: Bowden
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D003513:Cycloheximide / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000502:physiology; D004790:Enzyme Induction / Q000187:drug effects; D004792:Enzyme Precursors / Q000096:biosynthesis* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D008297:Male; D008666:Metalloendopeptidases / Q000096:biosynthesis* / Q000235:genetics; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000502:physiology; D012460:Sulfasalazine / Q000494:pharmacology; D013859:Thiocarbamates / Q000494:pharmacology; D015534:Trans-Activators / Q000502:physiology; D015533:Transcriptional Activation / Q000187:drug effects; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D004792:Enzyme Precursors; D007375:Interleukin-1; D015850:Interleukin-6; D016328:NF-kappa B; D009363:Neoplasm Proteins; D011500:Protein Synthesis Inhibitors; D011759:Pyrrolidines; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D013859:Thiocarbamates; D015534:Trans-Activators; C020972:pyrrolidine dithiocarbamic acid; D012460:Sulfasalazine; D003513:Cycloheximide; D008666:Metalloendopeptidases; C099583:promatrilysin