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Cytokine. 2000 Oct;12(10):1469-79.

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.

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Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, NH 03755, USA.


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.

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