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Role of CD38 in myometrial Ca²⁺ transients: modulation by progesterone

¹Signal Transduction Laboratory, Departments of Anesthesiology and Internal Medicine, and ²Department of Physiology and Mayo Clinic and Foundation, Rochester, Minnesota 55905; and ³Trudeau Institute, Saranac Lake, New York 12983

Submitted 11 March 2004 ; accepted in final form 16 August 2004

	ABSTRACT

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Oxytocin-induced Ca²⁺ transients play an important role in myometrial contractions. Here, using a knockout model, we found that the enzyme CD38, responsible for the synthesis of the second messenger cyclic ADP-ribose (cADPR), plays an important role in the oxytocin-induced Ca²⁺ transients and contraction. We also observed that CD38 is necessary for TNF--increased agonist-stimulated Ca²⁺ transients in human myometrial cells. We provide experimental evidence that the TNF- effect is mediated by increased expression of the enzyme CD38. First, we observed that TNF- increased oxytocin-induced Ca²⁺ transients and CD38 expression in human myometrial cells. Moreover, using small interference RNA technology, we observed that TNF- stimulation of agonist-induced Ca²⁺ transients was abolished by blocking the expression of CD38. In control experiments, we observed that activation of the component of the TNF- signaling pathway, NF-B, was not affected by the treatments. Finally, we observed that the effects of TNF- on CD38 cyclase and oxytocin-induced Ca²⁺ transients are abolished by progesterone. In conclusion, we provide the first experimental evidence that CD38 is important for myometrial Ca²⁺ transients and contraction. Moreover, CD38 is necessary for the TNF--mediated augmentation of agonist-induced Ca²⁺ transients in myometrial cells. We propose that the balance between cytokines and placental steroids regulates the expression of CD38 in vivo and cell responsiveness to oxytocin.

cyclic adenosine diphosphate-ribose; small interference ribonucleic acid; endoplasmic reticulum; ryanodine channel; tumor necrosis factor-

Intracellular Ca²⁺ concentration ([Ca²⁺]_i) regulation is a key factor in the modulation of uterine contraction (1, 2, 4, 14–16, 21–24, 26). To date, the mechanisms regulating [Ca²⁺]_i homeostasis in human myometrial cells have not been completely elucidated (21–24, 26). Understanding the signaling pathways regulating agonist-stimulated [Ca²⁺]_i transients in myometrial cells is imperative for the development of new therapeutic approaches to treat pathophysiological myometrial contraction. Oxytocin is a naturally occurring peptide responsible for myometrial contraction during labor (21–24, 26). Oxytocin is also frequently used as a pharmacological agonist to increase uterine contraction during dysfunctional labor (21–24, 26). Oxytocin-induced uterine contraction is initiated by an increase in [Ca²⁺]_i (21–24, 26). In myometrium, both influx of extracellular Ca²⁺ and mobilization of Ca²⁺ from intracellular stores are important for the generation of oxytocin-stimulated [Ca²⁺]_i transients in myometrial cells (21–24, 26). We have recently shown that cyclic ADP-ribose (cADPR) plays an important role in the oxytocin-induced Ca²⁺ transients in cultured human myometrial cells (1). cADPR is a newly described second messenger that controls [Ca²⁺]_i homeostasis in many cells (11–13, 16, 20).

Furthermore, we and others (1, 8, 27) also observed that cytokines such as TNF- can increase the expression of components of the cADPR pathway, namely the cADPR-synthesizing enzyme CD38. In addition, we have also shown that oxytocin-induced Ca²⁺ transients are augmented by TNF- (1). We then proposed that cytokines modulate the oxytocin-induced Ca²⁺ transients by increasing synthesis of cADPR (Fig. 1). However, whether CD38 is indeed important for agonist-induced myometrial Ca²⁺ transients is not known. Moreover, no direct demonstration of the role of CD38 in the TNF--mediated augmentation of oxytocin-induced Ca²⁺ transients has been published to date. Here, using cultured CD38-deficient (CD38 knockout) myometrial cells and using small interference RNA (SiRNA) technology, we clearly demonstrate that CD38 plays an important role in oxytocin-induced Ca²⁺ transients and is necessary for TNF--augmented agonist responsiveness. Additionally, we explored the interactions between cytokines and placental steroids. We found that progesterone is a potent inhibitor of the effects of TNF- on CD38 activity and oxytocin-induced Ca²⁺ transients. We propose that an important balance between placental steroids and cytokines may regulate the expression of CD38 in vivo and may play an important role in the preparation of the myometrium for labor.

View larger version (17K): [in this window] [in a new window]   Fig. 1. Schema of working hypothesis. We propose that the augmentation of agonist-stimulated intracellular Ca2+ transients induced by TNF- is mediated by increased expression of CD38, the enzyme responsible for the synthesis of the new nucleotide second messenger cyclic ADP-ribose (cADPR). SR, sarcoplasmic reticulum; [Ca2+]i, intracellular Ca2+ concentration.

	MATERIALS AND METHODS

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Cultured myometrial cell from CD38 wild-type and knockout mice. CD38 knockout mice (C57BL/6J.129 CD38^–/–, N12 back cross) were produced as described previously (19) and maintained in the Trudeau Institute Animal Breeding facility in accordance with all Trudeau Institute Animal Care and Use Committee guidelines. Culture of myometrial cells was performed as described above for the human myometrium.

Cyclase activity. ADP-ribosyl cyclase activity was measured using the nicotinamide-guanine dinucleotide (NGD) technique as previously described (5). Enzyme preparations were incubated in a medium containing 0.2 mM NGD, 0.25 M sucrose, and 40 mM Tris·HCl (pH 7.2) at 37°C. Activity was determined using a fluorometric assay at 300-nm excitation and 410-nm emission (7). In key experiments, results were also confirmed with the use of NAD, which is the natural substrate of the enzyme.

Hydrolase activity. Hydrolase activity was determined as described before (5, 7), using cADPR as a substrate. Briefly, cells were incubated with 100 µM cADPR, and the degradation of cADPR was determined using HPLC methodology.

Immunoprecipitation and Western blot. Human myometrial cell extracts were incubated in lysis buffer containing 0.05% IGEPAL-CA 630, 20 mM EDTA, 20 mM NaCl, 20 mM Tris, pH 7.0, 10% (vol/vol) protein G-Sepharose, and a 1:100 dilution of mouse monoclonal antibody against human CD38 (cat. no. SC 7325, Santa Cruz Biotechnology) for 4 h at 4°C. After 7.5% SDS-PAGE, protein was electroblotted onto polyvinylidene difluoride (PVDF) membrane, blocked with 5% nonfat milk overnight, and probed with a 1:100 dilution of goat polyclonal antibody against human CD38 (cat. no. SC 7048, Santa Cruz Biotechnology) for 4 h. The immunoreactive bands were detected using a 1:20,000 dilution of horseradish peroxidase-conjugated anti-goat IgG (cat. no. SC 2020, Santa Cruz Biotechnology) as secondary antibody and an enhanced chemiluminescence detection system. Western blot in mice myometrium was performed with the antibody sc-7049 Ab from Santa Cruz Biotechnology, which reacts with mouse CD38.

Measurement of CD38 mRNA expression and RT-PCR. A total of from 0.5 to 1 µg of mRNA was isolated using an Invitrogen kit (FastTrack 2.0 Kit, K1593-03) according to the manufacturer's instructions. cDNA was synthesized at 42°C for 50 min using 0.05 µg of oligo(dT) and 50 U of SuperScript II RT (11904-018, GIBCO-BRL). For PCR, a 2-µl aliquot of each cDNA solution was added to a reaction medium containing 0.2 mM dNTP, 50 mM MgCl₂, 0.25 U of Taq polymerase, and 0.2 µM CD38 primers. Reactions were performed in a DNA thermal cycler, with 40 cycles at 94°C for 45 s, 55°C for 60 s, and 72°C for 90 s. Human CD38 primers were 5'-ACCCCGCCTGGAGCCCTATG-3' and 5'-GCTAAAACAACCACAGCGACTGG-3'. As housekeeping mRNA, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) primers were used under the same conditions as described for CD38.

Inhibition of CD38 expression by siRNA technique. Downregulation of CD38 transcription was performed using oligonucleotide templates for human CD38 designed as by Munshi et al. (17), using a silencer siRNA contruction kit (cat. no. 1620, Ambion, Austin, TX) according to the manufacturer's instructions. Primers targeting region 27 were sense 5'-AGGACTGCAGCAACAACCCTTcctgtctc-3' and antisense 5'-GGGTTGTTGCTGCAGTCCTTTcctgtctc-3'. siRNA oligonucleotides were transfected into myometrial cells by use of a siPORT Amine transfection kit (cat. no. 1630, Ambion). Briefly, cells were incubated in SmBM containing siPORT Amine and 25 nM CD38 siRNA for 4 h and then supplemented with SmBM containing 10% FBS for 48 h. Negative controls of transfection were performed using siPORT Amine in the absence of any siRNA or the presence of 10 nM CD38 siRNAs (nonsense, cat. no. 1630, Ambion) as recommended by the manufacturer's instructions. Incubation procedures for GAPDH and nonsense siRNA-transfected cells were as for CD38-transfected cells. After the SiRNA treatment, cells were made quiescent for 12 h and then treated with or without 50 ng/ml TNF- for 24 h.

"Global" [Ca²⁺]_i imaging in human myometrial cells. Cultured human myometrial cells were plated on glass coverslips coated with rat tail collagen and incubated for 1–2 h at 37°C in 5% CO₂. Exclusion of Trypan blue was used to determine cell viability (>90%). Some cell samples were immunostained for anti-smooth actin to determine the relative proportion of myocytes and fibroblasts (50:1 ratio). Coverslips with attached cells were incubated with fura 2-AM (Molecular Probes, Eugene, OR) at 37°C for 30 min and then placed on an open slide chamber (Warner Instruments, Hamden, CT) mounted on a Nikon Diaphot inverted microscope. The chamber was perfused with HBSS at 2–3 ml/min at room temperature. Calcium measurements were determined using Metafluor software (Universal Imaging) and averaging changes in fluorescent ratio of 50 different individual cells by the following equation: [Ca²⁺] = K_d·(F_min/F_max)·[(R – visc·R_min)/(visc·R_max – R)], where K_d is the apparent dissociation constant (224 nM at room temperature), F_min, R_min, F_max, and R_max are the fluorescent values at 380 nm and 340/380-nm ratios in the absence of Ca²⁺ and saturating Ca²⁺, respectively, R is equivalent to the ratio of fluorescent intensity at 340/380 nm minus the background, and visc is the viscosity value of the cytoplasm (visc = 1). With the parameters described above, autofluorescence was not significant in our cells.

NF-B activation. Human uterine smooth muscle cells were grown on 100-mm Petri dishes by use of DMEM containing 10% FBS for 24 h before transfection. Cells were washed once in PBS, and medium was changed to DMEM containing 0% FBS. The CD38 and GAPDH (control) siRNA/siPort complexes (25 nM siRNA final concentration) were prepared according to the manufacturer's protocol (Ambion). SiRNAs were added to the cells and incubated for 4 h under normal culture conditions. Fresh growth medium was then added, and cells were grown for 48 h. Cells were washed once in PBS, and medium was change to DMEM containing 0% FBS for 24 h. TNF- (50 ng/ml final concentration) was then added for 10 min and the nuclear fraction prepared following cell lysis. The NF-B activation was determined by ELISA assay according to the manufacturer's instructions (Active Motif, Carlsbad, CA). Results were expressed as optical density (OD) of the nuclear extract. In control cells, provided by the manufacturer, the NF-B activation observed with 20 ng/ml TNF- was 67 ± 8 times (from 0.003 to 0.2 OD after incubation with TNF-).

Force generation in wild-type and CD38 knockout mouse uterine muscle strips. In summary, uterine smooth muscle strips were dissected, and 0.3- to 0.5-mm-wide strips of uterus isolated from wild-type and CD38 knockout mice were mounted in a Güth muscle research system (Scientific Instruments). Samples were mounted in a quartz tissue cuvette between length and force transducers by stainless steel microforceps. Signals were recorded via a data acquisition board (AT-MIO-16-L9, National Instruments) and software (Labview, National Instruments) running on a personal computer. The strips were initially perfused at 1 ml/min with physiological saline solution aerated with 95% O₂-5% CO₂. After stabilization, the strips were tested with 1 nM oxytocin.

Detection of cADPR levels in myometrium by cycling assay. One quarter to one gram of mouse myometrial tissue or human myometrial cells were frozen in liquid N₂, pulverized into a powder, and extracted with 5% trichloroacetic acid (TCA) at 4°C. TCA was removed with water-saturated ether. The aqueous layer containing the cADPR was removed and adjusted to pH 8 with 20 mM sodium phosphate. To remove nucleotides except cADPR, a mixture containing hydrolytic enzymes was added to the samples with the following final concentrations: 0.44 U/ml pyrophosphatase, 12.5 U/ml alkaline phosphatase, 0.0625 U/ml NADase, 2.5 mM MgCl₂, and 20 mM sodium phosphate, pH 8.0. The detection of cADPR was performed by our adaptation of the cycling method (5).

Materials. All other reagents, of the highest purity grade available, were supplied by Sigma Chemical (St. Louis, MO), except when stated otherwise. 3-Deaza-cADPR was also from Sigma Chemical.

Statistics. The reported experiments were repeated at least three to six times when appropriate; data are expressed as means ± SE or SD. One- or two-way ANOVA was used to evaluate statistical significance; P values <0.05 were considered significant.

	RESULTS AND DISCUSSION

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Role of CD38 on myometrial Ca²⁺ transients: use of CD38 knockout mice. It has been previously shown that myometrial cells express CD38 and produce cADPR, which in turn induces [Ca²⁺]_i release through the RyR channel (1, 5, 7, 9). However, to date, no direct demonstration of the role of the CD38 on agonist-induced Ca²⁺ transients in myometrium has been shown. Here, using the CD38 knockout mouse model, we found that oxytocin-induced Ca²⁺ transients are at least partially dependent on the presence of CD38 (Fig. 2). First, we observed that myometrial tissue from CD38 knockout mice lacks CD38, the ADP-ribosyl cyclase activity, and cADPR itself (Fig. 2, A–C). Furthermore, we obtained freshly isolated myometrial cells from both control and CD38 knockout mice. We observed that the apparent threshold for the oxytocin-induced intracellular Ca²⁺ transient was decreased severalfold in the CD38 knockout mice (Fig. 2D). In fact, both the peak [Ca²⁺]_i and the total Ca²⁺ increase induced by oxytocin were decreased in CD38 knockout mice (Fig 2D, inset). These results are similar to those reported on CD38 knockout pancreatic cells (10). We also observed that the decreased oxytocin-induced Ca²⁺ transients in CD38 knockout mice could be reversed by the incubation of cells with the nonhydrolyzable analog of cADPR 3-deaza-cADPR (25) (Fig. 2E). Finally, we also observed that oxytocin-induced contraction was impaired in myometrial strips isolated from uterus of CD38 knockout mice (Fig. 2F). Although the loss of CD38 clearly affected the oxytocin-induced Ca²⁺ transients and contraction, neither the gestation nor the labor patterns were different in control and CD38 knockout mice (data not shown). Whether this indicates that compensatory mechanisms are operative in the absence of CD38 or whether CD38 is indeed not necessary for labor in mice is not known. It is important to notice that deficiency in either oxytocin or its receptor has no significant impact on the onset and duration of labor in mice (21). Although these data may indicate that oxytocin is not necessary for labor in mice, there is very strong evidence that supports a physiological and pharmacological role for oxytocin in labor (21).

View larger version (24K): [in this window] [in a new window]   Fig. 2. Role of CD38 on oxytocin-induced Ca2+ transients. A: Western blot of wild-type control C57BL/6J mice (CTL) and CD38 knockout mice (KO). B: cyclase activity as measured using nicotinamide-guanine dinucleotide as substrate in CTL and CD38 KO mice. C: cADPR levels were determined in CTL and KO mice. D: dose dependence of oxytocin (OT)-induced Ca2+ transients in CTL (filled bars) and KO mice (open bars). E: effect of treatment of CTL and KO myometrial cells with 1 µM 3-deaza-cADPR (3-DcADPR), a potent hydrolysis-resistant analog of cADPR (25). Cells were incubated with 3-DcADPR for 30 min before addition of 1 nM oxytocin. F: oxytocin-induced contraction in uterine strips isolated from CTL and KO mice. Contraction was induced by addition of 1 nM oxytocin. [Ca2+]i values reported in D and E represent peak Ca2+ release induced by oxytocin. Basal [Ca2+]i values were 89 ± 8 nM. *Statistically different from control. Each experiment was repeated 4 times in triplicate.

Role of CD38 on TNF--augmented agonist-induced [Ca²⁺]_i transients in human myometrial cells.

In the present study, siRNA technology was used to blunt the TNF--induced increase in CD38 expression and thereby assess the role of CD38 on the TNF- augmentation of the oxytocin-induced [Ca²⁺]_i response. siRNA can bind specifically to target RNA and increase its degradation, leading to a specific decrease in protein expression. We treated human myometrial cells with siRNA for CD38, GAPDH, and a negative control CD38 nonsense siRNA. We found no effect of the CD38 siRNA treatment on the basal level of the CD38 cyclase activity, CD38 protein expression, and CD38 mRNA levels (Figs. 3 and 4). These results are probably due to a low turnover of CD38 protein, mRNA, or expression rate of the CD38 gene under basal conditions. In contrast, treatment of human myometrial cells with TNF- caused a threefold increase in CD38 cyclase activity, CD38 protein, and mRNA (Figs. 3 and 4). This TNF--induced increase in CD38 expression was completely blocked by treatment of cells with CD38 siRNA, but not by the nonsense CD38 siRNA (Figs. 3A and 4) or by blocking the GAPDH expression using a GAPDH-specific siRNA (data not shown).

View larger version (21K): [in this window] [in a new window]   Fig. 3. Effect of CD38-targeted small interference RNA (siRNA) on the effect of TNF- on CD38 cyclase activity. A: cells were treated without (control) or with CD38 siRNA, as described in MATERIALS AND METHODS. After treatment with siRNA, cells were treated or not (CTL) with 50 ng/ml TNF- for 24 h, after incubation cyclase activity was measured as described in the legend of Fig. 2. B: intracellular level of cADPR was determined in control cells and in cells treated with 50 ng/ml TNF- for 24 h in the absence (TNF- alone) or in the presence of CD38-specific siRNA (TNF + CD38 siRNA). Results are means of 3 or 4 experiments. *Statistically different from control.

View larger version (53K): [in this window] [in a new window]   Fig. 4. Effect of CD38-targeted siRNA on expression of CD38 in human myometrial cells. Human myometrial cells were treated with siRNA as described in MATERIALS AND METHODS, after which, cells were treated with 50 ng/ml TNF- for 24 h, as described. Cells were scraped, and protein and RNA were extracted. Protein was subjected to Western blot analysis of CD38, and RNA was used for RT-PCR of CD38 and GAPDH, as described in MATERIALS AND METHODS. A: Western blot for CD38. B: RT-PCR analysis for CD38 mRNA levels. C: the ratio of the densitometry for the RT-PCR for CD38 and GAPDH. We observed no effect of TNF- on the expression of GAPDH mRNA. Experiments in A and B are representative of 3 independent experiments; graph in C is average and SD of 3 independent experiments. *Statistically different from control.

As described above, treatment of human myometrial cells with TNF- leads to a twofold increase in the peak and plateau of the [Ca²⁺]_i response induced by oxytocin (Fig. 5). As shown in Fig. 5, blocking the expression of CD38 with the CD38 siRNA leads to a complete blunting of the TNF- augmentation of the peak [Ca²⁺]_i response induced by oxytocin. In contrast, the other siRNAs tested had no effect on TNF- augmentation of oxytocin effects (Fig. 5). These results clearly indicate that TNF- augmentation of the oxytocin-induced [Ca²⁺]_i response in human myometrial cells is dependent on increased expression of CD38. Furthermore, treatment of control or CD38-specific siRNA-treated cells did not impair the NF-B activation induced by TNF-. In fact, incubation of control or CD38-specific siRNA-treated cells with 50 ng/ml TNF- led to a 50-fold increase of the NF-B activity (from 0.003 to 0.16 OD in control and from 0.004 to 0.17 OD in siRNA-treated cells). We attempted to use the CD38 knockout mice to confirm these data; however, treatment of mouse myometrial cells with TNF- led to no change in the expression and activity of the CD38 cyclase (data not shown).

View larger version (26K): [in this window] [in a new window]   Fig. 5. Effect of CD38-targeted siRNA on TNF- augmentation of oxytocin-stimulated [Ca2+]i release in human myometrial cells. A: cells were made quiescent and then treated without (control) or with 50 ng/ml TNF- for 24 h. After treatment, cells were loaded with fura 2-AM, and release of intracellular calcium was initiated with 1 µM oxytocin and measured as described in MATERIALS AND METHODS. B: before treatment with TNF- and oxytocin as described in A, cells were treated with CD38 siRNA as described in MATERIALS AND METHODS. C: average and SD of 3 independent experiments. Results are expressed as % of control. No significant differences were observed between control cells with and without siRNA treatment. However, TNF--augmented oxytocin-induced Ca2+ transient was completely abolished by treatment of cells with CD38 siRNA, but not with the negative control nonsense siRNA. Basal [Ca2+]i value was 40 ± 12 nM. *Statistically different from control.

In conclusion, our results clearly indicate that CD38 plays an important role in inducing Ca²⁺ transients in oxytocin-stimulated mouse and human myometrial cells and also show that expression of the enzyme CD38 is necessary for TNF- augmentation of oxytocin-induced [Ca²⁺]_i response in human myometrial cells. The TNF- augmentation of oxytocin-induced [Ca²⁺]_i response in myometrial smooth muscle cells is likely related to an increased synthesis of cADPR by CD38, leading to increased sensitivity of the ryanodine channels to Ca²⁺-induced Ca²⁺ release (Fig. 1). Because TNF- augmentation of [Ca²⁺]_i transients to agonists has been implicated in several pathophysiological situations, including preterm labor, asthma, and renal diseases (1, 9, 27), we believe that this information may lead to a better understanding and development of novel therapeutic strategies for these conditions. Finally, we observed that the effects of TNF- on cyclase activity and agonist-induced Ca²⁺ transients are blocked by progesterone. Progesterone has multiple effects on myometrial cells; it appears that progesterone has important properties as a key factor to maintain myometrial cell quiescence (21). In fact, progesterone has been shown to decrease the expression of oxytocin receptor in myometrial cells. Here, we propose that, in addition to other previously reported effects, modulation of the expression of CD38 by progesterone may play an important role in the mechanism of progesterone-induced myometrial cell quiescence.

	GRANTS

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This research was supported in part by the Mayo Foundation and by the Foundation of Anesthesia Research.

	ACKNOWLEDGMENTS

 
We thank Dr. Claudia C. S. Chini for expert help with the development and use of siRNA technology in our laboratory.

	FOOTNOTES

 

Address for reprint requests and other correspondence: E. N. Chini, Dept. of Anesthesiology, Mayo Clinic and Foundation, Rochester, MN 55905 (E-mail: Chini.eduardo{at}mayo.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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