Regulation of store-operated Ca²⁺entry by CD38 in human airway smooth muscle

Abstract

(11,15,20,26,38,39,46) or by plasma membrane Ca 2ϩ influx.TNF␣, a potent proinflammatory cytokine found in bronchoalveolar lavage fluid (12) and sputum (50) from asthmatics, has been implicated as a mediator in the pathophysiology of asthma (45, 51, 52) and chronic obstructive pulmonary disease (8, 16). Indeed, TNF␣ has been shown to enhance ASM contractility (13,43,47 (11,20,46) as well as via ryanodine receptor (RyR) channels (15, 26), the latter resulting from increased levels of the novel second messenger cyclic ADP ribose (cADPR) (27,39). cADPR, in turn, is synthesized and degraded by the bifunctional ectoenzyme CD38 via ADP ribosyl cyclase and cADPR hydrolase activities, respectively (22). Indeed, the CD38/cADPR pathway has been implicated in [Ca 2ϩ ] i regulation in ASM (39, 57) and intestinal (30, 31), uterine (7, 53), and vascular (17, 25) smooth muscles. Recent studies suggest that the CD38/cADPR signaling pathway contributes to TNF␣-induced augmentation of [Ca 2ϩ ] i responses in ASM (14). Such an effect is thought to result from an increase in cADPRinduced Ca 2ϩ mobilization from the SR. However, this does not explain the effect of TNF␣ on both peak and plateau responses. While it is likely that SR Ca 2ϩ release is augmented by TNF␣, whether Ca 2ϩ influx is also increased remains to be determined.Ca 2ϩ influx in ASM can occur through voltage-gated (59), receptor-operated (33), and/or store-operated channels (6). In the last case, store-operated Ca 2ϩ entry (SOCE) is triggered by depletion of SR Ca 2ϩ stores (6,41,42,49,55,56). We and others have shown that different transient receptor potential channel (TRPC) isoforms are expressed in ASM (6,58). In a recent study using human ASM, we further demonstrated that TNF␣ treatment increases SOCE (58). TNF␣ treatment also increases CD38 expression. Studies in other cell types suggest that CD38 itself can also regulate SOCE (10, 21). Whether altered CD38 expression contributes to TNF␣-induced changes in Ca 2ϩ influx is not known. In the present study, we hypothesized that the effects of TNF␣ treatment on CD38 expression and SOCE in human ASM cells are linked. Accordingly, we examined the effects of CD38 overexpression vs. knockdown of CD38 expression [via specific small interfering RNA (siRNA)] on TNF␣-induced enhancement of SOCE. METHODSHuman ASM cells. Human bronchi were obtained from discarded surgical specimens in accordance with procedures reviewed and approved (as well as deemed exempt from Human Subjects classification under 45CFR 46) by the Mayo Clinic Institutional Review Board. The techniques for isolation of ASM cells from bronchi have

Effects of the Inflammatory Cytokines TNF-α and IL-13 on Stromal Interaction Molecule–1 Aggregation in Human Airway Smooth Muscle Intracellular Ca2+ Regulation

“…TNF-a has been known to increase agonist-induced [Ca 21 ] i response and contractility in ASM (1,6,22,25). Our recent studies also showed that TNF-a increases SOCE in human ASM cells (11,22). Similarly, IL-13 enhances agonist-induced [Ca 21 ] i responses in human ASM (26), and increases airway contractility in mouse and rat tracheas (27).…”

“…Upon sensing SR Ca 21 depletion, STIM1 oligomerizes with adjacent STIM1 proteins via the SAM domain, and moves within the SR membrane to enhance its proximity to the PM, where STIM1 interacts with Orai1 and transient receptor potential cation channels to form clusters, thus activating these PM channels to induce SOCE (24). Although much of the information on STIM1 was derived from nonexcitable cells and expression systems, STIM1 has been demonstrated in human ASM cells, and is implicated in the regulation of [Ca 21 ] i responses (11,21,22). The knockdown of STIM1 results in reduced SOCE after store depletion, whereas the overexpression of STIM1 dramatically increases SOCE in human ASM cells (21).…”

“…Several inflammatory cytokines such as TNF-a and IL-13 mediate their effects in airway disease by enhancing airway smooth muscle (ASM) intracellular Ca 21 concentration ([Ca 21 ] i ) (1-6), which triggers a diverse range of cellular processes, including ASM contraction (7)(8)(9). Elevations in [Ca 21 ] i in ASM cells normally occur through both Ca 21 influx across the plasma membrane (PM) and release from intracellular sarcoplasmic reticulum (SR) Ca 21 stores (8,(10)(11)(12)(13)(14)(15)(16).…”

“…Ca 21 influx in ASM cells can occur through voltage-gated and receptor-gated channels on the PM, as well as by storeoperated Ca 21 channels that are activated by the depletion of SR stores (7,10,11,(17)(18)(19). Ca 21 release from the SR occurs via both inositol 1,4,5-trisphosphate receptor (IP 3 R) channels and ryanodine receptor (RyR) channels on the SR membrane in ASM.…”

NAD+-Consuming Enzymes in the Regulation of Lung Immune Responses

“…In vitro studies showed that CD38 expression and its enzymatic activities are increased by TNF-, IFN-, IL-1 and IL-13 ( Fig. 2) [93][94][95]. TNF--induced CD38 expression is transcriptionally regulated and involves NF-B-dependent andindependent mechanisms [96].…”