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.
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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.
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.
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