Jayasinghe, Varuna, Joshi, Radhika, Joshi, Taruna, Paracha, Tamkeen, Kooi, Cora, Mostafa, Mahmoud, Bauer, Carla, Charlton, Steven, Iartchouk, Oleg, Maillet, Ashley, Morris, Melody, Ruda, Vera, Sandham, David, Wang, Yanqun, Newton, Robert and Giembycz, Mark (2025) Genomic crosstalk between carbachol, a muscarinic receptor agonist, and indacaterol, a long-acting, β2-adrenoceptor agonist, in human airway epithelial cells. Journal of Pharmacology and Experimental Therapeutics, 392 (6). p. 103579. ISSN 0022-3565

Abstract

Many patients with chronic obstructive pulmonary disease (COPD) are susceptible to recurrent exacerbations. Long-acting, muscarinic receptor antagonists protect against exacerbations suggesting that endogenous acetylcholine (ACh) could be a pro-inflammatory mediator. This idea was explored by determining if carbachol (CCh), a stable ACh analog, was a genomic stimulus in BEAS-2B bronchial epithelial cells. The ability of CCh to interact with indacaterol (Ind), a long-acting, β2-adrenoceptor agonists (LABA), was also assessed because sympathomimetic bronchodilators can promote the expression of adverse-effect genes in airway structural cells that are often regulated by the same transcription factors. Checkerboard assays using BEAS-2B cells expressing a cAMP response element luciferase reporter determined that CCh was a weak stimulus but interacted with Ind in a supra-additive manner. Likewise, mRNA-seq revealed that CCh regulated only 20 genes in BEAS-2B cells whereas Ind and Ind+CCh were powerful genomic stimuli affecting 869 and 1027 unique mRNAs, respectively. Of those, 39 genes were induced by Ind+CCh in a supra-additive manner; for the remainder, the interaction was either additive or infra-additive. Functional annotation of the Ind-regulated transcriptome identified transcription and signaling as dominant themes with gene ontology (GO) terms associated with inflammation and immune processes being highly represented. A comparable GO signature was obtained in the presence of CCh; however, the number, magnitude and duration of gene expression changes were markedly enhanced. If genomic interactions occur between a LABA and ACh in vivo, then this may lead to the expression of adverse-effect genes that, paradoxically, could maintain features of lung pathology in COPD.

Item Type:	Article
Date Deposited:	18 Jul 2025 00:45
Last Modified:	18 Jul 2025 00:45
URI:	https://oak.novartis.com/id/eprint/55946