Skip Navigation
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

National Institute of Environmental Health Sciences

Use this QR code to view the newest version of this document
Use this QR code to view the newest version of this document

Your Environment. Your Health.

Publication Detail

Title: Diacylglycerol kinase ζ promotes allergic airway inflammation and airway hyperresponsiveness through distinct mechanisms.

Authors: Singh, Brenal K; Lu, Wen; Schmidt Paustian, Amanda M; Ge, Moyar Q; Koziol-White, Cynthia J; Flayer, Cameron H; Killingbeck, Sara S; Wang, Nadan; Dong, Xinzhong; Riese, Matthew J; Deshpande, Deepak A; Panettieri Jr, Reynold A; Haczku, Angela; Kambayashi, Taku

Published In Sci Signal, (2019 09 03)

Abstract: Asthma is a chronic allergic inflammatory airway disease caused by aberrant immune responses to inhaled allergens, which leads to airway hyperresponsiveness (AHR) to contractile stimuli and airway obstruction. Blocking T helper 2 (TH2) differentiation represents a viable therapeutic strategy for allergic asthma, and strong TCR-mediated ERK activation blocks TH2 differentiation. Here, we report that targeting diacylglycerol (DAG) kinase zeta (DGKζ), a negative regulator of DAG-mediated cell signaling, protected against allergic asthma by simultaneously reducing airway inflammation and AHR though independent mechanisms. Targeted deletion of DGKζ in T cells decreased type 2 inflammation without reducing AHR. In contrast, loss of DGKζ in airway smooth muscle cells decreased AHR but not airway inflammation. T cell-specific enhancement of ERK signaling was only sufficient to limit type 2 airway inflammation, not AHR. Pharmacological inhibition of DGK diminished both airway inflammation and AHR in mice and also reduced bronchoconstriction of human airway samples in vitro. These data suggest that DGK is a previously unrecognized therapeutic target for asthma and reveal that the inflammatory and AHR components of asthma are not as interdependent as generally believed.

PubMed ID: 31481522 Exiting the NIEHS site

MeSH Terms: Animals; Asthma/enzymology; Asthma/genetics; Asthma/immunology*; Bronchoconstriction/drug effects; Bronchoconstriction/genetics; Bronchoconstriction/immunology; Cell Differentiation/drug effects; Cell Differentiation/genetics; Cell Differentiation/immunology; Diacylglycerol Kinase/genetics; Diacylglycerol Kinase/immunology*; Diacylglycerol Kinase/metabolism; Enzyme Inhibitors/pharmacology; Humans; Inflammation/enzymology; Inflammation/genetics; Inflammation/immunology*; MAP Kinase Signaling System/drug effects; MAP Kinase Signaling System/genetics; MAP Kinase Signaling System/immunology; Mice, Knockout; Myocytes, Smooth Muscle/drug effects; Myocytes, Smooth Muscle/enzymology; Myocytes, Smooth Muscle/immunology; Piperidines/pharmacology; Quinazolinones/pharmacology; Respiratory Hypersensitivity/enzymology; Respiratory Hypersensitivity/genetics; Respiratory Hypersensitivity/immunology*; Signal Transduction/drug effects; Signal Transduction/genetics; Signal Transduction/immunology; Th2 Cells/drug effects; Th2 Cells/enzymology; Th2 Cells/immunology

Back
to Top