Negative feed-forward control of TNF by tristetraprolin (ZFP36) is limited by the mitogen-activated protein kinase phosphatase, DUSP1: implications for regulation by glucocorticoids [Signal Transduction]

November 6th, 2015 by Shah, S., Mostafa, M. M., McWhae, A., Traves, S. L., Newton, R.

Tumor necrosis factor α (TNF) is central to inflammation and may play a role in the pathogenesis of asthma. The 3′-untranslated region of the TNF transcript contains AU-rich elements (AREs) that are targeted by the RNA-binding protein, tristetraprolin (ZFP36), which is itself up-regulated by inflammatory stimuli, to promote mRNA degradation. Using primary human bronchial epithelial (HBE) and pulmonary epithelial A549 cells, we confirm that interleukin-1β (IL1B) induces expression of dual-specificity phosphatase 1 (DUSP1), ZFP36 and TNF. While IL1B-induced DUSP1 is involved in feedback control of MAPK pathways, ZFP36 exerts negative (incoherent) feed-forward control of TNF mRNA and protein expression. DUSP1 silencing increased IL1B-induced ZFP36 expression at 2h and profoundly repressed TNF mRNA at 6h. This was partly due to increased TNF mRNA degradation, an effect that was reduced by ZFP36 silencing. This confirms a regulatory network, whereby DUSP1-dependent negative feedback control reduces feed-forward control by ZFP36. Conversely, while DUSP1 over-expression and inhibition of MAPKs prevented IL1B-induced expression of ZFP36, this was associated with increased TNF mRNA expression at 6h, an effect that was predominantly due to elevated transcription. This points to MAPK-dependent feed-forward control of TNF involving ZFP36-dependent and -independent mechanisms. In terms of repression by dexamethasone, neither silencing of DUSP1, ZFP36, nor both together, prevented the repression of IL1B-induced TNF expression thereby demonstrating the need for further repressive mechanisms by anti-inflammatory glucocorticoids. In summary, these data illustrate why understanding the competing effects of feedback and feed-forward control is relevant to the development of novel anti-inflammatory therapies.
  • Posted in Journal of Biological Chemistry, Publications
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