IL-1ra Secreted by ATP-Induced P2Y₂Negatively Regulates MUC5AC Overproduction via PLCβ3 during Airway Inflammation

Abstract

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/P2Y2 complex secretes many cytokines and chemokines to regulate airway inflammation, among which IL-1 receptor antagonist (IL-1ra) downregulates MUC5AC gene expression via the inhibition of Gαq-induced Ca2+ signaling. IL-1ra inhibited IL-1α protein expression and secretion, and vice versa. Interestingly, ATP/P2Y2-induced IL-1ra and IL-1α secretion were both mediated by PLCβ3. A dominant-negative mutation in the PDZ-binding domain of PLCβ3 inhibited ATP/P2Y2-induced IL-1ra and IL-1α secretion. IL-1α in the presence of the ATP/P2Y2 complex activated the ERK1/2 pathway in a greater degree and for a longer duration than the ATP/P2Y2 complex itself, which was dramatically inhibited by IL-1ra. These findings suggest that secreted IL-1ra exhibits a regulatory effect on ATP/P2Y2-induced MUC5AC gene expression, through inhibition of IL-1α secretion, to maintain the mucus homeostasis in the airway. Therefore, IL-1ra could be an excellent modality for regulating inflamed airway microenvironments in respiratory diseases.

Airborne particulate matter increases MUC5AC expression by downregulating Claudin-1 expression in human airway cells

“…This is an important finding, because ERK1/2 is critical signaling protein to increase the MUC5AC gene expression. In our previous reports, negative regulatory proteins (SHP-2 and IL-1ra) attenuate ERK1/2 activation to abolish MUC5AC gene expression in inflamed cells ( 24 ). Thus, understating the effects of ERK1/2 and Claudin-1 function is expected to provide effective information of the working mechanism of CLB 2.0 toxicity, as well as for the development of innovative therapeutic medication against destructive human health roles of air pollution inhalation.…”

“…However, there is no evidence that mucus hypersecretion and overproduction may affect PM-induced airway inflammation in the human respiratory track. MUC5AC has been considered inflammatory mucin because many inflammatory mediators, air pollutants, and pathogens increased MUC5AC overproduction and hypersecretion to progress inflamed microenvironment ( 22 – 24 ), whereas MUC1 has been considered anti-inflammatory mucin to maintain homeostasis ( 17 – 20 ). In this study, we suggest that CLB 2.0 disrupts the balance between the inflammatory condition and homeostasis to make inflamed condition in the airway.…”

Functional deficiency in endogenous interleukin‐1 receptor antagonist in patients with febrile infection‐related epilepsy syndrome

“…IL1RA is translated from 5 distinct isoforms that give rise to 2 secreted and 2 intracellular variants (isoforms 4 and 5 only differ upstream of the translational start site). Importantly, so‐called intracellular forms of IL1RA are secreted in response to adenosine triphosphate and other triggers and serve as acute response molecules . To determine whether the reduced levels of intracellular IL1RA protein were due to aberrant expression of specific IL1RN isoforms in the index FIRES patient, we analyzed expression of the secreted (isoform 1 and 4/5) and intracellular (isoforms 2 and 3) IL1RN gene products by RT‐PCR.…”

Purinergic Signalling: Therapeutic Developments

“…Mucin hypersecretion is stimulated in various respiratory diseases and silencing of MUC8 by siRNA increased P2Y 2 R-induced airway inflammation ( Cha et al, 2015 ). P2Y 2 R have also been claimed to downregulate MUC5AC gene expression ( Jeong et al, 2016 ). Nucleotides released during airway inflammation activate P2Y 6 R leading to further release of inflammatory cytokines ( Hao et al, 2014 ).…”