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Regulation of the cd38 promoter in human airway smooth muscle cells by TNF-α and dexamethasone
© Tirumurugaan et al. 2008
Received: 05 December 2007
Accepted: 14 March 2008
Published: 14 March 2008
CD38 is expressed in human airway smooth muscle (HASM) cells, regulates intracellular calcium, and its expression is augmented by tumor necrosis factor alpha (TNF-α). CD38 has a role in airway hyperresponsiveness, a hallmark of asthma, since deficient mice develop attenuated airway hyperresponsiveness compared to wild-type mice following intranasal challenges with cytokines such as IL-13 and TNF-α. Regulation of CD38 expression in HASM cells involves the transcription factor NF-κB, and glucocorticoids inhibit this expression through NF-κB-dependent and -independent mechanisms. In this study, we determined whether the transcriptional regulation of CD38 expression in HASM cells involves response elements within the promoter region of this gene.
We cloned a putative 3 kb promoter fragment of the human cd38 gene into pGL3 basic vector in front of a luciferase reporter gene. Sequence analysis of the putative cd38 promoter region revealed one NF-κB and several AP-1 and glucocorticoid response element (GRE) motifs. HASM cells were transfected with the 3 kb promoter, a 1.8 kb truncated promoter that lacks the NF-κB and some of the AP-1 sites, or the promoter with mutations of the NF-κB and/or AP-1 sites. Using the electrophoretic mobility shift assays, we determined the binding of nuclear proteins to oligonucleotides encoding the putative cd38 NF-κB, AP-1, and GRE sites, and the specificity of this binding was confirmed by gel supershift analysis with appropriate antibodies.
TNF-α induced a two-fold activation of the 3 kb promoter following its transfection into HASM cells. In cells transfected with the 1.8 kb promoter or promoter constructs lacking NF-κB and/or AP-1 sites or in the presence of dexamethasone, there was no induction in the presence of TNF-α. The binding of nuclear proteins to oligonucleotides encoding the putative cd38 NF-κB site and some of the six AP-1 sites was increased by TNF-α, and to some of the putative cd38 GREs by dexamethasone.
The EMSA results and the cd38 promoter-reporter assays confirm the functional role of NF-κB, AP-1 and GREs in the cd38 promoter in the transcriptional regulation of CD38.
CD38 is a pleiotropic protein that has enzymatic and receptor functions [1–3]. It is a ~45-kDa glycosylated transmembrane protein, with an extracellular domain that has an enzyme activity which generates cyclic ADP-ribose (cADPR) and ADPR from nicotinamide adenine dinucleotide (NAD) . CD38 is expressed in different cells including airway smooth muscle (ASM) cells, where its expression is confined to the plasma membrane . In ASM cells, CD38/cADPR signaling has a role in the regulation of intracellular calcium ([Ca2+]i) [5–7]. Previous studies from our laboratory showed that CD38 expression and its enzymatic activities are augmented by TNF-α and IL-13, cytokines that are implicated in the pathogenesis of inflammatory airway diseases such as asthma [5, 8]. The regulation of CD38 expression by TNF-α requires NF-κB activation and involves MAPK signaling in ASM cells [9, 10].
Glucocorticoids are used in the treatment of asthma  which regulate gene expression via the glucocorticoid receptor (GR). Upon activation by ligand binding, the GR translocates to the nucleus and acts either as a transcription factor or as an inhibitor of transcription factors such as NF-κB or AP-1. We have previously shown that TNF-α-induced CD38 expression in ASM cells is inhibited by glucocorticoids through a mechanism that involves decreased NF-κB activation .
Putative binding sites for AP-1, NF-B and GRE in the cd38 promoter.
NF-B binding site
-1728 to -1719
-2915 to -2909
-2835 to -2829
-2798 to -2789
-1041 to -1035
-993 to -987
-151 to -145
-2662 to -2658
-1398 to -1393
-1069 to -1063
-881 to -875
Tris base, glucose, HEPES and TNF-α were purchased from Sigma Chemical (St. Louis, MO). Hanks' balanced salt solution (HBSS) and Dulbecco's modified Eagle's medium (DMEM), Trizol, Lipofectamine™ 2000, Superscript III reverse transcriptase and the 1 kb DNA ladder were obtained from Invitrogen (Carlsbad, CA). Dual-Luciferase Reporter assay system, pGL3 basic vector, pRL-TK plasmid, GoTaqR Green Master Mix and EMSA kit were purchased from Promega (Madison, WI). QuickChange Site-Directed Mutagenesis kit was obtained from Stratagene (La Jolla, CA). The nuclear extraction kit was purchased from Active Motif (Carlsbad, CA). Recombinant human glucocorticoid receptor protein (RP-500) was obtained from Affinity Bioreagents (Golden, CO). Antibodies for p65 or p50 subunit of NF-κB, c-jun and c-fos were purchased from Santa Cruz Biotechnology (Santa Cruz, CA).
Promoter-luciferase reporter constructs and site directed mutagenesis
Sequences of the primers for the cd38 putative NF-κB and AP1–4 binding sites.
5'-GTGGAAGACAGTATGG C GATTCCTCAAAGATCTAGAACC-3'
5'-GGTTCTAGATCTTTGAGGAATC G CCATACTGTCTTCCAC-3'
5'-CTTGGCATCATCTTTGACT TG TCTCTTTCTTGCAAATGC-3'
5'-GCATTTGCAAGAAAGAGA CA AGTCAAAGATGATGCCAAG-3'
Sequence analysis of the cd38 promoter
The GeneQuest module of Lasergene 6.0 program from DNASTAR was used to identify the potential transcription factor binding sites in the cd38 promoter. The 3 kb sequence of the cd38 promoter was analyzed using GeneQuest for the potential transcription factor binding sites using tfd.dat file. Analysis revealed six AP-1 binding sites, one NF-κB binding site and four GRE binding sites within the cd38 promoter. The putative transcription factor binding sites on the cd38 promoter are shown in Table 1.
Human Airway Smooth Muscle Cell culture
Human airway smooth muscle (HASM) isolated from the trachealis muscle and propagated as described previously [9, 10]. were used in this study. The cells were plated at a density of 1.0 × 104 cells/cm2 and were cultured in DMEM supplemented with 10% FBS, 2 mM L-glutamine, 100 U/ml of penicillin, 0.1 mg/ml of streptomycin, and 0.25 μg/ml of amphotericin B. HASM cells were transfected as described below, then 24 hrs following transfection they were growth-arrested by maintaining them for at least 24 hrs in arresting medium containing no serum, but in the presence of transferrin and insulin prior to TNF-α (50 ng/ml) or dexamethasone (1 μM) treatment and measurement of luciferase reporter activity.
Transient transfections were performed with Lipofectamine™ 2000 according to the manufacturer's instructions. Cells (0.5–1 × 105) in 500 μl of growth medium without antibiotics were plated one day before transfection. For the transfection, 0.8 μg of the vector DNA and 2 μl of Lipofectamine™ 2000 in 50 μl of Opti-MEM® were mixed gently and incubated for 5 min at room temperature. Diluted DNA and lipofectamine were mixed and incubated for 20 min at room temperature to form complexes which were added to each well, and incubated at 37°C for 6 hrs. The cells were growth-arrested 24 hrs following transfection before exposing to TNF-α and dexamethasone. The cells were collected for luciferase reporter activity (described below).
Luciferase reporter gene transactivation assay
Reporter gene assays were performed 24 hrs after transfection. Cell lysates were subjected to the Dual-Luciferase Reporter assay system and luciferase activities were measured with a luminometer (Lumat LB9507; Berthold). Cells were washed twice with phosphate-buffered saline (PBS) with no calcium and magnesium, and covered (0.1 ml/well) with Passive Lysis Buffer (Promega). The cells were then scraped, the lysate transferred to microcentrifuge tubes, which was mixed by vortexing for 15 s, then passed a few times through a needle and used for the reporter assay. A 20 μl aliquot of the lysate was mixed with 100 μl of luciferase assay reagent and placed in a luminometer to measure the firefly luciferase activity. The fluorescence was quenched by the addition of the Stop and Glo buffer and Renilla luciferase activity was measured after a 2 second delay. Firefly luciferase activities were normalized to Renilla luciferase activity to account for transfection efficiency. Samples were analyzed in triplicate and the experiment was repeated at least twice.
Nuclear protein extraction
Nuclear extracts were prepared from growth-arrested HASM cells at confluence. The media were aspirated and washed with ice-cold PBS containing phosphatase inhibitors and the cells were scraped in 3 ml of the same buffer. The cells were pelletted by centrifugation at 1000 × g for 5 minutes and the supernatant discarded. The cells were resuspended in 500 μl 1× hypotonic buffer by pipetting several times, transferred to a chilled microcentrifuge tube and incubated for 15 mins on ice. Detergent (25 μl) was added, vortexed for 10 sec and pelleted by centrifugation at 14,000 × g for 30 sec at 4°C. The supernatant was removed and the nuclear pellet was resuspended in 50 μl of complete lysis buffer and vortexed for 10 sec. The mixture was incubated on ice for 30 min, vortexed briefly and pelleted at 14,000 × g for 10 min at 4°C. The supernatant (nuclear fraction) was aliquoted, protein content measured and stored at -80°C until use.
Electrophoretic mobility shift assay (EMSA)
Sequences of the Oligonucleotides used in the EMSAs.
HASM cells isolated from three different donors were used in the experiments. The experiments involving EMSA and transient transfections of the constructs were repeated three times. The samples were compared by one-way ANOVA with Bonferroni's test for multiple comparisons. GraphPad PRISM statistical software program was used for statistical analyses and significance established at P value of ≤ 0.05.
NF-κB, AP-1 and Glucocorticoid Receptor binding to the cd38 promoter
Activation of the cd38 promoter requires NF-κB and AP-1, and is inhibited by dexamethasone
Airway hyperresponsiveness to non-specific stimuli is a hallmark of asthma. In this regard, airway smooth muscle has a role in the regulation of airflow and in maintaining airway caliber. Airway smooth muscle contractility requires the elevation of intracellular calcium and the CD38/cADPR signaling pathway has a central role in calcium homeostasis . A previous study from our laboratory demonstrated that CD38 expression is up-regulated by the proinflammatory cytokine TNF-α resulting in an increased intracellular calcium response to multiple agonists . The increased CD38 expression is down-regulated by the anti-inflammatory glucocorticoid dexamethasone through inhibition of NF-κB . In this study, we characterized a 3 kb fragment that functions as a promoter of the cd38 gene. We also show that the cd38 promoter contains one NF-κB, six AP-1, and four GRE putative binding sites. TNF-α caused activation of the 3 kb promoter fragment, which is decreased when the NF-κB and/or the AP1–4 sites were mutated. The EMSA studies confirmed direct binding of NF-κB and AP-1 to putative cd38 binding sites. Dexamethasone reversed the TNF-α-induced activation of the 3 kb promoter and increased the binding of GR to consensus and putative cd38 GREs. These studies demonstrate an important role of NF-κB and AP-1 in the regulation of CD38 expression in HASM cells. Furthermore, glucocorticoids decrease CD38 expression transcriptionally by directly binding to the putative cis-acting binding sites and also by interfering with the transcription factors.
The cd38 gene has been localized on chromosome 4 in human and chromosome 5 in the mouse . The CD38 protein is encoded by a >80 kb length gene comprising of 8 exons. Studies from other laboratories have revealed binding sites for several transcription activating factors in the cd38 gene [17, 18]. Previous studies have shown the absence of a canonical TATA or CAAT box sequences in the cd38 promoter region, suggesting that transcription can be initiated at multiple sites . However, TATA-less promoters with transcription start sites such as an initiator (Inr) sequence or binding sites for the PU.1 transcription factor have been described in myeloid and B cells . The G/C rich region upstream of ATG may also support the initiation of transcription. In addition, consensus binding sites for T cell transcription factor (TCF-1α), Ig gene box enhancer motifs (μE1, μE5 and κE2), nuclear factor-IL-6 and IFN-responsive factor-1 have been described . Kishimoto et al  have reported the DR5 repeat (TGACCCgaaagTGCCCC) within intron 1, which has a role in retinoic acid induction of CD38 expression in HL-60 cells. Studies from other laboratories have revealed a ~900 bp CpG island spanning exon 1 and the 5' end of intron 1 with a binding sequence for Sp1, a transcription factor that regulates the constitutive expression of CD38 . Furthermore, a glucocorticoid response element and an estrogen binding motif have also been described in the promoter region of cd38 . In support of a functional role of the estrogen binding motif within the promoter, our previous studies demonstrate the up-regulation of CD38 expression by estrogen in uterine smooth muscle [23–25]. Taken together, it is likely the transcriptional regulation of CD38 expression by these hormones may have a physiological role in uterine motility.
Inflammatory cytokines such as TNF-α, IL-1β and IFN-γ play an important role in diseases such as asthma [26, 27]. Previous investigations have demonstrated that the levels of inflammatory cytokines are elevated in the bronchoalveolar lavage fluid obtained from asthmatic subjects [26, 27]. TNF-α has been shown to increase the expression of a variety of genes resulting in functional changes in airway smooth muscle cells [28, 29]. Recent investigations from our laboratory have shown that the inflammatory cytokines increase the expression of CD38 in human airway smooth muscle cells [5, 7, 8]. The regulation of CD38 expression by TNF-α in HASM cells involves NF-κB and AP-1 activation and signaling through the p38 and JNK MAP kinases [9, 10]. TNF-α-induced CD38 expression in airway smooth muscle cells involves signaling via the TNFR1 receptor and IFNβ that is generated in response to TNF-α . Thus, the induction of CD38 expression by TNF-α may involve regulation by multiple transcription factors such as interferon regulatory factor-1, NF-κB, AP-1 and possibly others. In this context, sequence analysis of the cloned human cd38 promoter also reveals 4 putative binding sites for the transcription factor c/EBPβ, three of which are within a region upstream of the NF-κB site. The 1.8 kb truncated promoter construct that was not activated by TNF-α also contains these c/EBPβ sites. The role, if any, of this transcription factor in the regulation of CD38 expression in HASM cells remains to be determined.
Glucocorticoids are used extensively as anti-inflammatory therapy in asthma  and their mechanism(s) of action are complex . The nuclear translocation of the GR complex and its binding to specific DNA motifs results in both transactivation and repression of a variety of genes [12, 32–34]. The presence of GREs provides a basis for transcriptional regulation of CD38 expression. The GR complex also interferes with NF-κB binding to DNA [35, 36]., thereby decreasing the expression of genes that are regulated by this transcription factor. We have previously demonstrated inhibition of NF-κB activation by dexamethasone in HASM cells exposed to TNF-α . This inhibition results from decreased NF-κB expression and increased IκB expression following exposure to dexamethasone. This mechanism of regulation of NF-κB activation has been described in other cell systems [33, 37]. In preliminary studies, we have also noticed decreased AP-1 activation in TNF-α-stimulated cells by dexamethasone. The mechanism of glucocorticoid-mediated reduction of CD38 expression may involve steric hindrance for the binding of NF-κB and AP-1 to their binding sites and/or interference with transactivation. The actions of glucocorticoids have been demonstrated for the NF-κB- and AP-1-mediated regulation of other genes [34, 38–43].
In this study, we have identified 4 glucocorticoid response elements in the putative promoter region of the cd38 gene as well as response elements for AP-1 and NF-κB (Table 1). Inhibition of NF-κB or AP-1 activation, or MAPK signaling using pharmacological and molecular tools has confirmed their role in the regulation of CD38 expression [9, 10]. The identified putative sites for AP-1 and GRE also exhibit strong binding in EMSA upon exposure to TNF-α and dexamethasone respectively. The AP1–4 site (residing between -2798 to -2789 bp) that shows very strong binding also appears to be functionally important in the activation of the promoter, since mutation of this site profoundly affected TNF-α-induced activation of CD38 expression. With respect to NF-κB, mutation of the only identifiable binding site also resulted in abolition of CD38 transcription. It is worth noting that binding to this site was weak compared to the consensus NF-κB sequence binding, although competition with the unlabelled putative sequence effectively abolished the strong binding to the consensus sequence. In the presence of dexamethasone, there was complete reversal of TNF-α-induced activation of the promoter, indicating direct transcriptional regulation of CD38 expression by glucocorticoids in HASM cells. These findings implicate the importance of NF-κB and AP-1, and the GRE within the proximal promoter region in the regulation of CD38 gene expression. The results of promoter transfections and EMSAs with cd38 putative GREs demonstrate transcriptional repression of CD38 expression by glucocorticoids. However, glucocorticoids are also known to repress gene expression in HASM cells through inhibition of histone acetylation . Evidence for glucocorticoid resistance of CD38 expression in HASM cells has also been reported when a combination of cytokines is used as the stimulus as opposed to the single stimulus used in the present study. In this context, a recent study showed that in the combined presence of TNF-α and IFN-γ or IFN-β, CD38 expression in HASM cells becomes refractory to glucocorticoids . The mechanism appears to involve induction of the dominant negative GR-β. Thus, the glucocorticoid regulation of CD38 expression in airway smooth muscle cells is very complex and appears to depend on the stimulus or combination of stimuli used.
In a recent study, Sun et al described the structure of the promoter region of rabbit cd38 and provided evidence for the functional regulation of CD38 expression in osteoblast and osteoclast cell lines . In a region encompassing 1.5 kb of the promoter obtained from a rabbit genomic DNA library, the authors identified potential binding sites for SP-1, AP-1, and AP-4. Using promoter-reporter assays similar to those described in the present studies, with a 1.5 kb promoter and several deletion mutants, they were able to demonstrate a functional AP-1 site in the 1.0 kb promoter fragment. There also appears to be cell-type specific activation of the promoter as shown by studies with deletion mutagenesis.
In the present study, we describe NF-κB and AP-1 binding motifs within the cd38 promoter that exhibit very strong binding of nuclear proteins, mutations of which decrease promoter activation and hence may be functionally relevant. Our results also support the role of multiple transcription factors in the regulation of CD38 expression in HASM cells. Furthermore, we demonstrate a direct transcriptional control of CD38 expression by glucocorticoids, although we have not identified specific GREs within the proximal promoter region involved in this regulation. The fact that CD38 expression is regulated by cytokines and transcription factors that are implicated in asthma, and inhibited by glucocorticoids which are a mainstay of asthma therapy makes this an attractive therapeutic target.
This study was supported by National Institutes of Health Grants HL-057498 (to M.S. Kannan), DA-11806 (to T.F. Walseth), HL-081824 and National Institute of Environmental Health Sciences (NIEHS) ES0135080 grants (to R.A. Panettieri), and a Grant-in-Aid from the University of Minnesota Graduate School (to M.S. Kannan).
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