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Prolonged activation of jun and collagenase genes by tumour necrosis factor-α

Abstract

Tumour necrosis factor-α (TNF-α) is secreted by macrophages in response to inflammation, infection and cancer1. Sublethal doses of recombinant TNF-α to rats causes cachexia, anaemia and inflammation2. TNF-α plays a major part in tissue inflammation3 and remodelling4 by stimulating production of collagenase. Cellular responses to TNF-a are initiated by binding to high-affinity cell surface receptors5,6. TNF-α then profoundly affects gene regulation, stimulating thefos, myc, interleukin-1 and interleukin-6 genes7-9 and inhibiting the type I collagen gene10. Here we demonstrate that TNF-α also stimulates collagenase gene transcription; this stimulation is mediated by an element of the gene that is responsive to the transcription factor AP-1, the major component of which (jun/AP-1) is encoded by the jun gene; and that TNF-α stimulates prolonged activation of jun gene expression. This prolonged induction of jun contrasts with its transient activation by the phorbol ester TPA and provides a physiological example of the ability of jun/AP-1 to stimulate its own transcription11. This may be a key mechanism for mediating at least some of the biological effects of TNF-α.

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Brenner, D., O'Hara, M., Angel, P. et al. Prolonged activation of jun and collagenase genes by tumour necrosis factor-α. Nature 337, 661–663 (1989). https://doi.org/10.1038/337661a0

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