IL-1ra Secreted by ATP-Induced P2Y2 Negatively Regulates MUC5AC Overproduction via PLCβ3 during Airway Inflammation

Autor: Jiwook Kim, Yu-Mi Yang, Bokyoum Kim, Kyoung Seob Song, Jee-Yeong Jeong, Joo Won Kim, Siejeong Ryu, Ju Deok Kim, Yusom Shin
Jazyk: angličtina
Rok vydání: 2016
Předmět:
Zdroj: Mediators of Inflammation, Vol 2016 (2016)
Mediators of Inflammation
MEDIATORS OF INFLAMMATION
ISSN: 1466-1861
0962-9351
Popis: Mucus secretion is often uncontrolled in many airway inflammatory diseases of humans. Identifying the regulatory pathway(s) of mucus gene expression, mucus overproduction, and hypersecretion is important to alleviate airway inflammation in these diseases. However, the regulatory signaling pathway controlling mucus overproduction has not been fully identified yet. In this study, we report that the ATP/P2Y2complex secretes many cytokines and chemokines to regulate airway inflammation, among which IL-1 receptor antagonist (IL-1ra) downregulatesMUC5ACgene expression via the inhibition of Gαq-induced Ca2+signaling. IL-1ra inhibited IL-1αprotein expression and secretion, and vice versa. Interestingly, ATP/P2Y2-induced IL-1ra and IL-1αsecretion were both mediated by PLCβ3. A dominant-negative mutation in the PDZ-binding domain of PLCβ3 inhibited ATP/P2Y2-induced IL-1ra and IL-1αsecretion. IL-1αin the presence of the ATP/P2Y2complex activated the ERK1/2 pathway in a greater degree and for a longer duration than the ATP/P2Y2complex itself, which was dramatically inhibited by IL-1ra. These findings suggest that secreted IL-1ra exhibits a regulatory effect on ATP/P2Y2-inducedMUC5ACgene expression, through inhibition of IL-1αsecretion, to maintain the mucus homeostasis in the airway. Therefore, IL-1ra could be an excellent modality for regulating inflamed airway microenvironments in respiratory diseases.
Databáze: OpenAIRE
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