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Journal of Allergy
Volume 2012 (2012), Article ID 289468, 8 pages
http://dx.doi.org/10.1155/2012/289468
Review Article

Altered CD38/Cyclic ADP-Ribose Signaling Contributes to the Asthmatic Phenotype

1Department of Veterinary and Biomedical Sciences, University of Minnesota, Saint Paul, MN 55108, USA
2Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
3Department of Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA

Received 2 August 2012; Revised 13 October 2012; Accepted 13 October 2012

Academic Editor: Michael M. Grunstein

Copyright © 2012 Joseph A. Jude et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

CD38 is a transmembrane glycoprotein expressed in airway smooth muscle cells. The enzymatic activity of CD38 generates cyclic ADP-ribose from β-NAD. Cyclic ADP-ribose mobilizes intracellular calcium during activation of airway smooth muscle cells by G-protein-coupled receptors through activation of ryanodine receptor channels in the sarcoplasmic reticulum. Inflammatory cytokines that are implicated in asthma upregulate CD38 expression and increase the calcium responses to contractile agonists in airway smooth muscle cells. The augmented intracellular calcium responses following cytokine exposure of airway smooth muscle cells are inhibited by an antagonist of cyclic ADP-ribose. Airway smooth muscle cells from CD38 knockout mice exhibit attenuated intracellular calcium responses to agonists, and these mice have reduced airway response to inhaled methacholine. CD38 also contributes to airway hyperresponsiveness as shown in mouse models of allergen or cytokine-induced inflammatory airway disease. In airway smooth muscle cells obtained from asthmatics, the cytokine-induced CD38 expression is significantly enhanced compared to expression in cells from nonasthmatics. This differential induction of CD38 expression in asthmatic airway smooth muscle cells stems from increased activation of MAP kinases and transcription through NF-κB, and altered post-transcriptional regulation through microRNAs. We propose that increased capacity for CD38 signaling in airway smooth muscle in asthma contributes to airway hyperresponsiveness.