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1 Department of Physiology & Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota, United States
2 Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, Minnesota, United States
3 Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, Minnesota, United States; Department of Physiology & Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota, United States
4 Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota, United States; Department of Physiology & Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota, United States
* To whom correspondence should be addressed. E-mail: sieck.gary{at}mayo.edu.
The ectoenzyme CD38 catalyzes synthesis and degradation of cyclic-ADP-ribose (cADPR) in airway smooth muscle (ASM). The pro-inflammatory cytokine TNF-alpha (TNF
), which enhances agonist-induced intracellular Ca2+ ([Ca2+]i) responses, has been previously shown to increases CD38 expression. In the present study, we tested the hypothesis that the effects of TNF on CD38 expression vs. changes in [Ca2+]i regulation in ASM cells are linked. Using isolated human ASM cells, CD38 expression was either increased (transfection) or knocked down (small interference RNA; siRNA), and [Ca2+]i responses to sarcoplasmic reticulum (SR) depletion (i.e. store-operated Ca2+ entry; SOCE) were evaluated in the presence vs. absence of TNF. Results confirmed that TNF significantly increased CD38 expression and ADP-ribosyl cyclase activity, an effect inhibited by CD38 siRNA, but unaltered by CD38 overexpression. CD38 suppression blunted, while overexpression enhanced, ACh-induced [Ca2+]i responses. TNF-induced enhancement of [Ca2+]i response to agonist was blunted by CD38 suppression, but enhanced by CD38 overexpression. Finally, TNF-induced increase in SOCE was blunted by CD38 siRNA, and potentiated by CD38 overexpression. Overall, these results indicate a critical role for CD38 in TNF induced enhancement of [Ca2+]i in human ASM cells, and potentially to TNF augmentation of airway responsiveness.
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