Regulator of G-Protein Signaling 4 Suppresses LPS-Induced MUC5AC Overproduction in the Airway

Abstract

Mucus overproduction and airway obstruction are common features in airway mucosal inflammation. The mechanism by which LPS induces MUC5AC overexpression, however, has not been fully explored. The aims of this study were twofold: first, to examine the ATP-dependent mechanism by which LPS induces MUC5AC gene expression, and second, to identify specific molecules that could suppress LPS-induced MUC5AC expression at a G-protein-coupled receptor level. Here, we suggest that LPS from Pseudomonas aeruginosa induces MUC5AC overproduction by both an ATP-dependent pathway and an ATP-independent pathway. In addition, we showed that Regulator of G-protein signaling (RGS) 4 plays as a suppressor for ATP-induced MUC5AC expression by interacting with Gaq in a GTP-dependent manner in vivo. These results give additional insights into the molecular mechanism of negative regulation of mucin overproduction and enhance our understanding of mucus hypersecretion during airway mucosal inflammation.

Airway smooth muscle in airway reactivity and remodeling: what have we learned?

“…Certainly, much work is needed to identify techniques or complementary drugs to target specific GRK isoforms or ␤-arrestins to enhance or maintain the functionality of particular bronchodilator therapies, be it ␤ 2 -agonists or bitter tastants and other novel therapies in the future. Along the lines of GRKs and ␤-arrestins, is the increasing recognition that regulators of G-protein signaling (RGS) may play a role in airway contractility (as well as remodeling) (49,64,289,290,340,343). A specific RGS usually prevents the continued activation of multiple G proteins, and thus upregulation or downregulation of RGS can have broad effects.…”

Silencing of MUC8 by siRNA increases P2Y2-induced airway inflammation

“…ATP secretion can be stimulated by hypoxia (22), LPS (28,29), or via autoregulation; thus, ATP can transfer inflammatory signals from inflamed cells to neighboring cells. This phenomenon is important because cells that take up ATP are known to secrete numerous cytokines that serve to augment inflammation in the local microenvironment.…”

“…However, P2X 7 is not expressed in normal human nasal epithelial cells (11) or in NCI-H292 cells (data not shown). Interestingly, P2Y 2 is highly expressed in airway epithelial cells (28). In addition, P2X 7 is a channel protein and P2Y 2 is a G q ␣ proteincoupled receptor (GPCR).…”

“…Although many studies have been performed, the mechanisms by which mucin expression is regulated and mucin secretion is stimulated in various respiratory diseases remain unclear (28). Although mucus overproduction and hypersecretion are frequently observed in a number of respiratory diseases, including rhinitis, sinusitis, asthma, chronic obstructive pulmonary disease, and cystic fibrosis (29), the exact physiological roles of each mucin in respiratory disease remain poorly defined.…”

“…In addition, ATP binding to the P2 receptor has been shown to induce the secretion of inflammatory cytokines (4,19,30). We previously showed that lipopolysaccharide (LPS) induces extracellular ATP secretion (28) and that this secreted ATP significantly enhances MUC5AC overproduction via a P2Y 2 -dependent mechanism (29). Several reports have demonstrated that P2X 7 is essential for ATP-induced cytokine secretion (4,7,31).…”