title: Negative Feed-forward Control of Tumor Necrosis Factor (TNF) by Tristetraprolin (ZFP36) Is Limited by the Mitogen-activated Protein Kinase Phosphatase, Dual-specificity Phosphatase 1 (DUSP1): IMPLICATIONS FOR REGULATION BY GLUCOCORTICOIDS.
abstract: 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 (also known as zinc finger protein 36 (ZFP36)), which is itself up-regulated by inflammatory stimuli, to promote mRNA degradation. Using primary human bronchial epithelial and pulmonary epithelial A549 cells, we confirm that interleukin-1β (IL1B) induces expression of dual-specificity phosphatase 1 (DUSP1), ZFP36, and TNF. Whereas 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 2 h and profoundly repressed TNF mRNA at 6 h. 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, whereas DUSP1 overexpression and inhibition of MAPKs prevented IL1B-induced expression of ZFP36, this was associated with increased TNF mRNA expression at 6 h, 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, silencing of ZFP36, nor silencing of 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.
authors.affiliation: From the Airways Inflammation Research Group, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta T2N 4Z6, Canada.
authors.forename: Suharsh
authors.initials: S
authors.lastname: Shah
authors.affiliation: From the Airways Inflammation Research Group, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta T2N 4Z6, Canada.
authors.forename: Mahmoud M
authors.initials: MM
authors.lastname: Mostafa
authors.affiliation: From the Airways Inflammation Research Group, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta T2N 4Z6, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: McWhae
authors.affiliation: From the Airways Inflammation Research Group, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta T2N 4Z6, Canada.
authors.forename: Suzanne L
authors.initials: SL
authors.lastname: Traves
authors.affiliation: From the Airways Inflammation Research Group, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta T2N 4Z6, Canada rnewton@ucalgary.ca.
authors.forename: Robert
authors.initials: R
authors.lastname: Newton
mesh_terms: D045744:Cell Line, Tumor; D003907:Dexamethasone / Q000494:pharmacology; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D020868:Gene Silencing / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000235:genetics; D053583:Interleukin-1beta / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D054852:Small Molecule Libraries / Q000494:pharmacology; D051816:Tristetraprolin / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D005938:Glucocorticoids; D053583:Interleukin-1beta; D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; D051816:Tristetraprolin; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1
keywords: DUSP1; anti-inflammatory; dual-specificity phosphoprotein phosphatase; feed-forward control; glucocorticoid; inflammation; mitogen-activated protein kinase (MAPK); tumor necrosis factor (TNF)