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.
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.
authors.affiliation: Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, NH 03755, USA.
authors.forename: A
authors.initials: A
authors.lastname: Barchowsky
authors.forename: D
authors.initials: D
authors.lastname: Frleta
authors.forename: M P
authors.initials: MP
authors.lastname: Vincenti
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016895:Culture Media, Serum-Free; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000201:enzymology; D005419:Flavonoids / Q000494:pharmacology; D017930:Genes, Reporter; D007093:Imidazoles / Q000494:pharmacology; D007375:Interleukin-1 / Q000378:metabolism / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis; D011725:Pyridines / Q000494:pharmacology; D011817:Rabbits; D015398:Signal Transduction; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D016895:Culture Media, Serum-Free; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D007375:Interleukin-1; D016328:NF-kappa B; D016755:Proto-Oncogene Proteins c-jun; D011725:Pyridines; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020781:Matrix Metalloproteinase 1; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one