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Prostaglandin E2, but not cAMP nor β2-agonists, induce tristetraprolin (TTP) in human airway smooth muscle cells

  • Peta Bradbury
  • Brijeshkumar S. Patel
  • Aylin Cidem
  • Cassandra P. Nader
  • Brian G. Oliver
  • Alaina J. AmmitEmail author
Original Research Paper
  • 42 Downloads

Abstract

Tristetraprolin (TTP) is an anti-inflammatory molecule known to post-transcriptionally regulate cytokine production and is, therefore, an attractive drug target for chronic respiratory diseases driven by inflammation, such as asthma and chronic obstructive pulmonary disease. Our recent in vitro studies in primary human airway smooth (ASM) cells have confirmed the essential anti-inflammatory role played by TTP as a critical partner in a cytokine regulatory network. However, several unanswered questions remain. While prior in vitro studies have suggested that TTP is regulated in a cAMP-mediated manner, raising the possibility that this may be one of the ways in which β2-agonists achieve beneficial effects beyond bronchodilation, the impact of β2-agonists on ASM cells is unknown. Furthermore, the effect of prostaglandin E2 (PGE2) on TTP expression in ASM cells has not been reported. We address this herein and reveal, for the first time, that TTP is not regulated by cAMP-activating agents nor following treatment with long-acting β2-agonists. However, PGE2 does induce TTP mRNA expression and protein upregulation in ASM cells. Although the underlying mechanism of action remains undefined, we can confirm that PGE2-induced TTP upregulation is not mediated via cAMP, or EP2/EP4 receptor activation, and occurred in a manner independent of the p38 MAPK-mediated pathway. Taken together, these data confirm that β2-agonists do not upregulate TTP in human ASM cells and indicate that another way in which PGE2 may achieve beneficial effects in asthma and COPD may be via upregulation of the master controller of inflammation—TTP.

Keywords

Tristetraprolin cAMP β2-agonists PGE2 Inflammation Asthma COPD 

Notes

Acknowledgements

Funded by the: Woolcock Emphysema Centre; National Health and Medical Research Council of Australia; Centre for Health Technologies, Faculty of Science, University of Technology Sydney; and the Rebecca Cooper Medical Research Foundation. The authors wish to thank our colleagues at the Woolcock Institute of Medical Research (especially Dikaia Xenaki) and acknowledge the collaborative effort of the cardiopulmonary transplant team and the pathologists at St Vincent’s Hospital, Sydney, and the thoracic physicians and pathologists at Royal Prince Alfred Hospital, Concord Repatriation Hospital and Strathfield Private Hospital and Healthscope Pathology, Sydney.

Author contributions

Conceived, designed, and performed the experiments: PB, BSP, AC, CPN, and AJA. Provision of ASM cells: BGO. Analysis and interpretation: PB and AJA. Wrote the paper: AJA.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

References

  1. 1.
    Prabhala P, Ammit A. Tristetraprolin and its role in regulation of airway inflammation. Mol Pharmacol. 2015;87:629–38.CrossRefGoogle Scholar
  2. 2.
    Prabhala P, Bunge K, Rahman MM, Ge Q, Clark AR, Ammit AJ. Temporal regulation of cytokine mRNA expression by tristetraprolin: dynamic control by p38 MAPK and MKP-1. Am J Physiol Lung Cell Mol Physiol. 2015;308:L973-80.CrossRefGoogle Scholar
  3. 3.
    Rahman MM, Rumzhum NN, Morris JC, Clark AR, Verrills NM, Ammit AJ. Basal protein phosphatase 2A activity restrains cytokine expression: role for MAPKs and tristetraprolin. Scientific reports. 2015;5:10063.CrossRefGoogle Scholar
  4. 4.
    Prabhala P, Bunge K, Ge Q, Ammit AJ. Corticosteroid-Induced. MKP-1 represses pro-inflammatory cytokine secretion by enhancing activity of tristetraprolin (TTP) in ASM cells. J Cell Physiol. 2016;231:2153–8.CrossRefGoogle Scholar
  5. 5.
    Giembycz MA, Kaur M, Leigh R, Newton R. A Holy Grail of asthma management: toward understanding how long-acting beta(2)-adrenoceptor agonists enhance the clinical efficacy of inhaled corticosteroids. Br J Pharmacol 2007.Google Scholar
  6. 6.
    Che W, Manetsch M, Quante T, Rahman MM, Patel BS, Ge Q, et al. Sphingosine 1-phosphate induces MKP-1 expression via p38 MAPK- and CREB-mediated pathways in airway smooth muscle cells. Biochim Biophys Acta. 2012;1823:1658–65.CrossRefGoogle Scholar
  7. 7.
    Manetsch M, Rahman MM, Patel BS, Ramsay EE, Rumzhum NN, Alkhouri H, et al. Long-acting beta2-agonists increase fluticasone propionate-induced mitogen-activated protein kinase phosphatase 1 (MKP-1) in airway smooth muscle cells. PLoS One. 2013;8:e59635.CrossRefGoogle Scholar
  8. 8.
    Patel BS, Prabhala P, Oliver BG, Ammit AJ. Inhibitors of phosphodiesterase 4, but not phosphodiesterase 3, increase beta2-agonist-induced expression of antiinflammatory mitogen-activated protein kinase phosphatase 1 in airway smooth muscle cells. Am J Respir Cell Mol Biol. 2015;52:634–40.CrossRefGoogle Scholar
  9. 9.
    Patel BS, Rahman MM, Baehring G, Xenaki D, Tang FS, Oliver BG, et al. Roflumilast N-oxide in combination with formoterol enhances the antiinflammatory effect of dexamethasone in airway smooth muscle cells. Am J Respir Cell Mol Biol. 2017;56:532–8.CrossRefGoogle Scholar
  10. 10.
    Jalonen U, Leppanen T, Kankaanranta H, Moilanen E. Salbutamol increases tristetraprolin expression in macrophages. Life Sci. 2007;81:1651–8.CrossRefGoogle Scholar
  11. 11.
    Brahma PK, Zhang H, Murray BS, Shu FJ, Sidell N, Seli E, et al. The mRNA-binding protein Zfp36 is upregulated by beta-adrenergic stimulation and represses IL-6 production in 3T3-L1 adipocytes. Obesity. 2012;20:40–7.CrossRefGoogle Scholar
  12. 12.
    Lebender LF, Prunte L, Rumzhum NN, Ammit AJ. Selectively targeting prostanoid E (EP) receptor-mediated cell signalling pathways: Implications for lung health and disease. Pulm Pharmacol Ther. 2018;49:75–87.CrossRefGoogle Scholar
  13. 13.
    Ammit AJ, Hoffman RK, Amrani Y, Lazaar AL, Hay DWP, Torphy TJ, et al. TNFa-induced secretion of RANTES and IL-6 from human airway smooth muscle cells: modulation by cAMP. Am J Respir Cell Mol Biol. 2000;23:794–802.CrossRefGoogle Scholar
  14. 14.
    Rumzhum NN, Ammit AJ. Prostaglandin E2 induces expression of MAPK phosphatase 1 (MKP-1) in airway smooth muscle cells. Eur J Pharmacol. 2016;782:1–5.CrossRefGoogle Scholar
  15. 15.
    Kwak SP, Hakes DJ, Martell KJ, Dixon JE. Isolation and characterization of a human dual specificity protein-tyrosine phosphatase gene. J Biol Chem. 1994;269:3596–604.Google Scholar
  16. 16.
    Johnson PR, McKay KO, Armour CL, Black JL. The maintenance of functional activity in human isolated bronchus after cryopreservation. Pulm Pharmacol. 1995;8:43–7.CrossRefGoogle Scholar
  17. 17.
    Rahman MM, Rumzhum NN, Hansbro PM, Morris JC, Clark AR, Verrills NM, et al. Activating protein phosphatase 2A (PP2A) enhances tristetraprolin (TTP) anti-inflammatory function in A549 lung epithelial cells. Cell Signal. 2016;28:325–34.CrossRefGoogle Scholar
  18. 18.
    Jalonen U, Paukkeri EL, Moilanen E. Compounds that increase or mimic cyclic adenosine monophosphate enhance tristetraprolin degradation in lipopolysaccharide-treated murine j774 macrophages. J Pharmacol Exp Ther. 2008;326:514–22.CrossRefGoogle Scholar
  19. 19.
    O’Neil JD, Ammit AJ, Clark AR. MAPK p38 regulates inflammatory gene expression via tristetraprolin: doing good by stealth. Int J Biochem Cell Biol. 2018;94:6–9.CrossRefGoogle Scholar
  20. 20.
    DuBois RN, McLane MW, Ryder K, Lau LF, Nathans D. A growth factor-inducible nuclear protein with a novel cysteine/histidine repetitive sequence. J Biol Chem. 1990;265:19185–91.Google Scholar
  21. 21.
    Kaneda N, Oshima M, Chung SY, Guroff G. Sequence of a rat TIS11 cDNA, an immediate early gene induced by growth factors and phorbol esters. Gene. 1992;118:289–91.CrossRefGoogle Scholar
  22. 22.
    Rataj F, Planel S, Desroches-Castan A, Le Douce J, Lamribet K, Denis J, et al. The cAMP pathway regulates mRNA decay through phosphorylation of the RNA-binding protein TIS11b/BRF1. Mol Biol Cell. 2016;27:3841–54.CrossRefGoogle Scholar
  23. 23.
    Fujino H, Salvi S, Regan JW. Differential regulation of phosphorylation of the cAMP response element-binding protein after activation of EP2 and EP4 prostanoid receptors by prostaglandin E2. Mol Pharmacol. 2005;68:251–9.Google Scholar
  24. 24.
    Venigalla RKC, Turner M. RNA-binding proteins as a point of convergence of the PI3K and p38 MAPK pathways. Front Immunol. 2012;3:398–8.CrossRefGoogle Scholar
  25. 25.
    Tang T, Scambler TE, Smallie T, Cunliffe HE, Ross EA, Rosner DR, et al. Macrophage responses to lipopolysaccharide are modulated by a feedback loop involving prostaglandin E2, dual specificity phosphatase 1 and tristetraprolin. Sci Rep. 2017;7:4350.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Woolcock Emphysema Centre, Woolcock Institute of Medical ResearchUniversity of SydneySydneyAustralia
  2. 2.School of Life Sciences, Faculty of ScienceUniversity of Technology SydneySydneyAustralia
  3. 3.Faculty of PharmacyUniversity of SydneySydneyAustralia
  4. 4.Respiratory Cellular and Molecular Biology, Woolcock Institute of Medical ResearchUniversity of SydneySydneyAustralia

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