CD38/cADPR Signaling Pathway in Airway Disease: Regulatory Mechanisms

Deepak A Deshpande,Alonso G P Guedes,Mathur S Kannan,Subbaya Subramanian,Richard Graeff,Timothy F Walseth,Soner Dogan

doi:10.1155/2018/8942042

Abstract

Asthma is an inflammatory disease in which proinflammatory cytokines have a role in inducing abnormalities of airway smooth muscle function and in the development of airway hyperresponsiveness. Inflammatory cytokines alter calcium (Ca2+) signaling and contractility of airway smooth muscle, which results in nonspecific airway hyperresponsiveness to agonists. In this context, Ca2+ regulatory mechanisms in airway smooth muscle and changes in these regulatory mechanisms encompass a major component of airway hyperresponsiveness. Although dynamic Ca2+ regulation is complex, phospholipase C/inositol tris-phosphate (PLC/IP3) and CD38-cyclic ADP-ribose (CD38/cADPR) are two major pathways mediating agonist-induced Ca2+ regulation in airway smooth muscle. Altered CD38 expression or enhanced cyclic ADP-ribosyl cyclase activity associated with CD38 contributes to human pathologies such as asthma, neoplasia, and neuroimmune diseases. This review is focused on investigations on the role of CD38-cyclic ADP-ribose signaling in airway smooth muscle in the context of transcriptional and posttranscriptional regulation of CD38 expression. The specific roles of transcription factors NF-kB and AP-1 in the transcriptional regulation of CD38 expression and of miRNAs miR-140-3p and miR-708 in the posttranscriptional regulation and the underlying mechanisms of such regulation are discussed.

Highlights

Asthma is an inflammatory disease in which proinflammatory cytokines have a role in inducing abnormalities of airway smooth muscle (ASM) function and in the development of airway hyperresponsiveness (AHR)
ASM cells obtained from subjects who died from an episode of asthma or subjects with a history of stable asthma show significantly enhanced expression of CD38 to low concentrations of TNF-α compared to expression in cells from nonasthmatics [5]. This is significant since the TNF-α axis does have a role in asthma that is refractory to current therapy, and TNF-α levels in bronchoalveolar lavage (BAL) fluid are elevated in patients with severe asthma [23,24,25,26]. These observations collectively indicate that the capacity for CD38/cADPR signaling in [Ca2+]i regulation and contractility of ASM is significantly greater in asthmatic ASM cells than in cells derived from nonasthmatic subjects
We demonstrated augmented CD38 expression, ADP-ribosyl cyclase activity, cADPR production, and [Ca2+]i responses to agonists in human ASM cells by IL-13 and TNF-α [2,3,4, 15, 16]

Summary

Introduction

Asthma is an inflammatory disease in which proinflammatory cytokines have a role in inducing abnormalities of airway smooth muscle (ASM) function and in the development of airway hyperresponsiveness (AHR). CD38 has been implicated in other human pathologies including in neuroinflammatory diseases, renal dysfunctions, neoplastic disorders, and viral infections (respiratory syncytial virus) [19,20,21,22] Inflammatory cytokines such as IL-13 and TNF-α, which are implicated in asthma, augment CD38 expression and cADPR-mediated Ca2+ release and increase contractility of ASM. These observations collectively indicate that the capacity for CD38/cADPR signaling in [Ca2+]i regulation and contractility of ASM is significantly greater in asthmatic ASM cells than in cells derived from nonasthmatic subjects This might arise due to altered CD38 expression and/or modulation of enzyme activities associated with CD38. This is the first report that describes rearrangements involving CD38 or deletions in patients with ASD

Regulation of CD38 Expression in ASM Cells

Posttranscriptional Regulation of CD38 Expression

Findings

Conclusions