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

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 antiinflammatory 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 β2agonists 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 longacting 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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“…PGE 2 also inhibited fibroblast migration, proliferation, collagen deposition, and myofibroblast differentiation in the lung ( 55 ). In vitro , PGE 2 decreased the expression of tenacin C and fibronectin by human fibroblast and ASM cells ( 56 ), reduced the proliferation of ASM cells derived from asthmatic patients ( 57 ), and upregulated the expression of the anti-inflammatory protein tristetraprolin in human ASM cells ( 58 ). Prior investigations of our group revealed that the instillation of glucagon induced a high production of PGE 2 into the lungs ( 59 ).…”