Title: Integration of the NF-kappaB and mitogen-activated protein kinase/AP-1 pathways at the collagenase-1 promoter: divergence of IL-1 and TNF-dependent signal transduction in rabbit primary synovial fibroblasts.
Authors: Barchowsky, A; Frleta, D; Vincenti, M P
Published In Cytokine, (2000 Oct)
Abstract: Collagenase-1 (MMP-1) is a protease that is expressed by stromal cells and that is involved in remodeling of the extracellular matrix. IL-1 and TNF-alpha enhance collagenase secretion by stromal cells, and chronic exposure of cells to these cytokines can contribute to connective tissue disease. In this study, we show that the NF-kappaB pathway is required for activation of collagenase-1 transcription in rabbit primary synovial fibroblasts (RSF). Although both IL-1 and TNF activate NF-kappaB in these cells, only IL-1 induces collagenase-1 transcription. We have reported previously that NF-kappaB and AP-1 cooperate to mediate IL-1-induced MMP-1 transcription. Here, we show that IL-1 is superior to TNF at inducing c-Jun synthesis, phosphorylation and binding activity in RSF. Similarly, IL-1 is more effective at activating the mitogen-activated protein kinases (MAPK), including the extracellular signal-regulated kinases (ERK), which are required for IL-1-induced MMP-1 transcription. Thus stimulation of the ERK and AP-1 pathways is an essential component of MMP-1 transcriptional activation, which is deficient in TNF-treated cells. These studies demonstrate cooperation between the MAPK and NF-kappaB signaling pathways for IL-1-dependent collagenase-1 transcription, and they define a dichotomy of IL-1- and TNF-elicited signaling that is relevant to cytokine-mediated connective tissue disease.
PubMed ID: 11023661
MeSH Terms: Animals; Blotting, Western; Culture Media, Serum-Free; Dose-Response Relationship, Drug; Enzyme Activation; Enzyme Inhibitors/pharmacology; Extracellular Matrix/metabolism; Fibroblasts/enzymology; Flavonoids/pharmacology; Genes, Reporter; Imidazoles/pharmacology; Interleukin-1/metabolism; Interleukin-1/pharmacology; MAP Kinase Signaling System*; Matrix Metalloproteinase 1/genetics; Matrix Metalloproteinase 1/metabolism*; Mitogen-Activated Protein Kinases/metabolism; NF-kappa B/genetics; NF-kappa B/metabolism*; Phosphorylation; Plasmids/metabolism; Promoter Regions, Genetic; Protein Binding; Proto-Oncogene Proteins c-jun/biosynthesis; Pyridines/pharmacology; Rabbits; Signal Transduction; Time Factors; Transcription Factor AP-1/genetics; Transcription Factor AP-1/metabolism*; Transcription, Genetic; Transcriptional Activation; Transfection; Tumor Necrosis Factor-alpha/metabolism; Tumor Necrosis Factor-alpha/pharmacology; p38 Mitogen-Activated Protein Kinases