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Modulation of Calcium Signaling by Interleukin-13 in Human Airway Smooth Muscle

Role of CD38/Cyclic Adenosine Diphosphate Ribose Pathway

Departments of Veterinary PathoBiology and Pharmacology, University of Minnesota, St. Paul; Department of Physiology, Mayo Clinic, Rochester, Minnesota; and Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Address correspondence to: Mathur S. Kannan, Professor of Pharmacology, Department of Veterinary PathoBiology, College of Veterinary Medicine, 205 Veterinary Science, 1971 Commonwealth Avenue, St. Paul, MN 55108. E-mail: kanna001{at}umn.edu

CD38/cyclic adenosine diphosphate ribose (cADPR) signaling plays an important role in the regulation of intracellular calcium responses to agonists in a variety of cells, including airway smooth muscle (ASM) cells. The present study was aimed at determining the effect of interleukin (IL)-13, a cytokine implicated in the pathogenesis of asthma, on CD38/cADPR signaling and to ascertain the contribution of CD38/cADPR signaling to IL-13–induced airway hyperresponsiveness. Human ASM cells maintained in culture were exposed to 50 ng/ml IL-13 for 22 h and levels of CD38 expression and intracellular calcium responses to agonists were measured. Treatment of human ASM cells with IL-13 resulted in increased CD38 expression as determined by real-time polymerase chain reaction, Western blot analysis, and indirect immunofluorescence. Increased CD38 expression was reflected as increased ADP-ribosyl cyclase activity in the ASM cell membranes. The net intracellular calcium responses to bradykinin, thrombin, and histamine were significantly (P 0.05) higher in cells treated with IL-13 compared with controls. Furthermore, 8-bromo-cADPR, a cADPR antagonist, attenuated IL-13–induced augmented intracellular calcium responses to agonists in human ASM cells. These findings indicate that the CD38/cADPR–dependent pathway has a major role in IL-13–induced modulation of calcium signaling in human ASM.

Abbreviations: 8-bromo-cyclic adenosine diphosphate ribose, 8br-cADPR • airway hyperresponsiveness, AHR • airway smooth muscle, ASM • bovine serum albumin, BSA • cyclic adenosine diphosphate ribose, cADPR • number of cycles required to achieve threshold fluorescence, C_t • cyclic guanosine diphosphoribose, cGDPR • human airway smooth muscle, HASM • Hanks' balanced salt solution, HBSS • interleukin, IL • nicotinamide adenine dinucleotide, NAD • reverse transcriptase–polymerase chain reaction, RT-PCR • T helper, Th