Pharmacological Stimulation of G-protein Coupled Receptor 40 Alleviates Cytokine-Induced Epithelial Barrier Disruption in Airway Epithelial Calu-3 Cells

Aekkacha Moonwiriyakit, Michael Koval, Chatchai Muanprasat

Int Immunopharmacol. 2019 Aug;73:353-361.

PMID: 31129422

Abstract:

Impairment of airway tight junctions induced by elevated levels of proinflammatory cytokines is implicated in the pathogenesis of inflammatory airway diseases. Pharmacological stimulation of G-protein coupled receptor (GPR) 40, a receptor of polyunsaturated fatty acids, have recently been shown to promote tight junction assembly in airway epithelial cells under non-inflammatory conditions. However, roles of GPR40 in regulating airway epithelial integrity in response to inflammatory insults are unknown. This study was aimed to investigate the effect of GPR40 stimulation on proinflammatory cytokine (TNFα and IL-1β)-induced tight junction disruption in human airway epithelial Calu-3 cells using GW9508, a GPR40 agonist. We found that stimulation of GPR40 by GW9508 attenuated the cytokine-induced airway epithelial barrier leakage as analyzed by measurements of transepithelial electrical resistance and transepithelial flux of fluorescently labeled dextran (molecular weight of 4 kDa). Furthermore, GW9508 prevented the cytokine-induced dislocalization of zonula occludens (ZO)-1, occludin and claudin-1. The barrier-protective effect of GW9508 was abolished by a GPR40 antagonist, but not a GPR120 antagonist. Immunofluorescence staining of NF-ĸB indicated that GW9508 had no effect on cytokine-induced NF-ĸB activation. Intriguingly, GW9508 inhibited cytokine-induced airway epithelial barrier disruption through suppression of extracellular signal-regulated kinase (ERK) phosphorylation in a phospholipase C (PLC) and calcium/calmodulin-dependent protein kinase kinase beta (CaMKKβ)-dependent manner. Collectively, this study uncovered the novel role of GPR40 in preventing cytokine-induced tight junction disruption in airway epithelial cells through mechanisms involving PLC-CaMKKβ-mediated suppression of ERK signaling. Pharmacological stimulation of GPR40 may be beneficial in the treatment of airway diseases.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP885101893-B	GW9508		885101-89-3	Price