- Open Access
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 Expression
- Glucocorticoid Receptor
- Electrophoretic Mobility Shift Assay
- Airway Smooth Muscle
- Airway Smooth Muscle Cell
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).
- Lee HC: Enzymatic functions and structures of CD38 and homologs. Chem Immunol 2000, 75:39–59.View ArticlePubMedGoogle Scholar
- Lee HC, Graeff RM, Walseth TF: ADP-ribosyl cyclase and CD38. Multi-functional enzymes in Ca+2 signaling. Adv Exp Med Biol 1997, 419:411–9.View ArticlePubMedGoogle Scholar
- Mehta K, Shahid U, Malavasi F: Human CD38, a cell-surface protein with multiple functions. FASEB J 1996, 10:1408–17.PubMedGoogle Scholar
- White TA, Johnson S, Walseth TF, Lee HC, Graeff RM, Munshi CB, Prakash YS, Sieck GC, Kannan MS: Subcellular localization of cyclic ADP-ribosyl cyclase and cyclic ADP-ribose hydrolase activities in porcine airway smooth muscle. Biochim Biophys Acta 2000, 1498:64–71.View ArticlePubMedGoogle Scholar
- Deshpande DA, Walseth TF, Panettieri RA, Kannan MS: CD38/cyclic ADP-ribose-mediated Ca2+ signaling contributes to airway smooth muscle hyper-responsiveness. FASEB J 2003, 17:452–4.PubMedGoogle Scholar
- White TA, Kannan MS, Walseth TF: Intracellular calcium signaling through the cADPR pathway is agonist specific in porcine airway smooth muscle. FASEB J 2003, 17:482–4.PubMedGoogle Scholar
- Deshpande DA, White TA, Dogan S, Walseth TF, Panettieri RA, Kannan MS: CD38/cyclic ADP-ribose signaling: role in the regulation of calcium homeostasis in airway smooth muscle. Am J Physiol Lung Cell Mol Physiol 2005, 288:L773–88.View ArticlePubMedGoogle Scholar
- Deshpande DA, Dogan S, Walseth TF, Miller SM, Amrani Y, Panettieri RA, Kannan MS: Modulation of calcium signaling by interleukin-13 in human airway smooth muscle: role of CD38/cyclic adenosine diphosphate ribose pathway. Am J Respir Cell Mol Biol 2004, 31:36–42.View ArticlePubMedGoogle Scholar
- Kang BN, Tirumurugaan KG, Deshpande DA, Amrani Y, Panettieri RA, Walseth TF, Kannan MS: Transcriptional regulation of CD38 expression by tumor necrosis factor-alpha in human airway smooth muscle cells: role of NF-kappaB and sensitivity to glucocorticoids. FASEB J 2006, 20:1000–2.View ArticlePubMedGoogle Scholar
- Tirumurugaan KG, Jude JA, Kang BN, Panettieri RA, Walseth TF, Kannan MS: TNF-alpha induced CD38 expression in human airway smooth muscle cells: role of MAP kinases and transcription factors NF-kappaB and AP-1. Am J Physiol Lung Cell Mol Physiol 2007, 292:L1385–95.View ArticlePubMedGoogle Scholar
- Barnes PJ: Drugs for asthma. Br J Pharmacol 2006,147(Suppl 1):S297–303.PubMedPubMed CentralGoogle Scholar
- Beato M: Gene regulation by steroid hormones. Cell 1989, 56:335–44.View ArticlePubMedGoogle Scholar
- Kishimoto H, Hoshino S, Ohori M, Kontani K, Nishina H, Suzawa M, Kato S, Katada T: Molecular mechanism of human CD38 gene expression by retinoic acid. Identification of retinoic acid response element in the first intron. J Biol Chem 1998, 273:15429–34.View ArticlePubMedGoogle Scholar
- Sun L, Iqbal J, Zaidi S, Zhu LL, Zhang X, Peng Y, Moonga BS, Zaidi M: Structure and functional regulation of the CD38 promoter. Biochem Biophys Res Commun 2006, 341:804–9.View ArticlePubMedGoogle Scholar
- Sugiyama T, Scott DK, Wang JC, Granner DK: Structural requirements of the glucocorticoid and retinoic acid response units in the phosphoenolpyruvate carboxykinase gene promoter. Mol Endocrinol 1998, 12:1487–98.View ArticlePubMedGoogle Scholar
- Scott DK, Stromstedt PE, Wang JC, Granner DK: Further characterization of the glucocorticoid response unit in the phosphoenolpyruvate carboxykinase gene. The role of the glucocorticoid receptor-binding sites. Mol Endocrinol 1998, 12:482–91.View ArticlePubMedGoogle Scholar
- Ferrero E, Saccucci F, Malavasi F: The making of a leukocyte receptor: origin, genes and regulation of human CD38 and related molecules. Chem Immunol 2000, 75:1–19.View ArticlePubMedGoogle Scholar
- Mehta K: Retinoid-mediated signaling in CD38 antigen expression. Chem Immunol 2000, 75:20–38.View ArticlePubMedGoogle Scholar
- Nata K, Takamura T, Karasawa T, Kumagai T, Hashioka W, Tohgo A, Yonekura H, Takasawa S, Nakamura S, Okamoto H: Human gene encoding CD38 (ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase): organization, nucleotide sequence and alternative splicing. Gene 1997, 186:285–92.View ArticlePubMedGoogle Scholar
- Ernst P, Smale ST: Combinatorial regulation of transcription. I: General aspects of transcriptional control. Immunity 1995, 2:311–9.View ArticlePubMedGoogle Scholar
- Ferrero E, Malavasi F: Human CD38, a leukocyte receptor and ectoenzyme, is a member of a novel eukaryotic gene family of nicotinamide adenine dinucleotide+-converting enzymes: extensive structural homology with the genes for murine bone marrow stromal cell antigen 1 and aplysian ADP-ribosyl cyclase. J Immunol 1997, 159:3858–65.PubMedGoogle Scholar
- Ferrero E, Saccucci F, Malavasi F: The human CD38 gene: polymorphism, CpG island, and linkage to the CD157 (BST-1) gene. Immunogenetics 1999, 49:597–604.View ArticlePubMedGoogle Scholar
- Dogan S, Deshpande DA, Kannan MS, Walseth TF: Changes in CD38 expression and ADP-ribosyl cyclase activity in rat myometrium during pregnancy: influence of sex steroid hormones. Biol Reprod 2004, 71:97–103.View ArticlePubMedGoogle Scholar
- Dogan S, White TA, Deshpande DA, Murtaugh MP, Walseth TF, Kannan MS: Estrogen increases CD38 gene expression and leads to differential regulation of adenosine diphosphate (ADP)-ribosyl cyclase and cyclic ADP-ribose hydrolase activities in rat myometrium. Biol Reprod 2002, 66:596–602.View ArticlePubMedGoogle Scholar
- Dogan S, Deshpande DA, White TA, Walseth TF, Kannan MS: Regulation of CD 38 expression and function by steroid hormones in myometrium. Mol Cell Endocrinol 2006, 246:101–6.View ArticlePubMedGoogle Scholar
- Riffo-Vasquez Y, Pitchford S, Spina D: Cytokines in airway inflammation. Int J Biochem Cell Biol 2000, 32:833–53.View ArticlePubMedGoogle Scholar
- Broide DH, Lotz M, Cuomo AJ, Coburn DA, Federman EC, Wasserman SI: Cytokines in symptomatic asthma airways. J Allergy Clin Immunol 1992, 89:958–67.View ArticlePubMedGoogle Scholar
- Ammit AJ, Lazaar AL, Irani C, O'Neill GM, Gordon ND, Amrani Y, Penn RB, Panettieri RA Jr: Tumor necrosis factor-alpha-induced secretion of RANTES and interleukin-6 from human airway smooth muscle cells: modulation by glucocorticoids and beta-agonists. Am J Respir Cell Mol Biol 2002, 26:465–74.View ArticlePubMedGoogle Scholar
- Amrani Y, Chen H, Panettieri RA Jr: Activation of tumor necrosis factor receptor 1 in airway smooth muscle: a potential pathway that modulates bronchial hyper-responsiveness in asthma? Respir Res 2000, 1:49–53.View ArticlePubMedPubMed CentralGoogle Scholar
- Tliba O, Panettieri RA Jr, Tliba S, Walseth TF, Amrani Y: Tumor necrosis factor-alpha differentially regulates the expression of proinflammatory genes in human airway smooth muscle cells by activation of interferon-beta-dependent CD38 pathway. Mol Pharmacol 2004, 66:322–9.View ArticlePubMedGoogle Scholar
- Chikanza IC, Kozaci D, Chernajovsky Y: The molecular and cellular basis of corticosteroid resistance. J Endocrinol 2003, 179:301–10.View ArticlePubMedGoogle Scholar
- Scheinman RI, Cogswell PC, Lofquist AK, Baldwin AS Jr: Role of transcriptional activation of I kappa B alpha in mediation of immunosuppression by glucocorticoids. Science 1995, 270:283–6.View ArticlePubMedGoogle Scholar
- Auphan N, DiDonato JA, Rosette C, Helmberg A, Karin M: Immunosuppression by glucocorticoids: inhibition of NF-kappa B activity through induction of I kappa B synthesis. Science 1995, 270:286–90.View ArticlePubMedGoogle Scholar
- Bamberger CM, Schulte HM, Chrousos GP: Molecular determinants of glucocorticoid receptor function and tissue sensitivity to glucocorticoids. Endocr Rev 1996, 17:245–61.View ArticlePubMedGoogle Scholar
- Verma IM, Stevenson JK, Schwarz EM, Van Antwerp D, Miyamoto S: Rel/NF-kappa B/I kappa B family: intimate tales of association and dissociation. Genes Dev 1995, 9:2723–35.View ArticlePubMedGoogle Scholar
- Karin M: New twists in gene regulation by glucocorticoid receptor: is DNA binding dispensable? Cell 1998, 93:487–90.View ArticlePubMedGoogle Scholar
- Doucas V, Shi Y, Miyamoto S, West A, Verma I, Evans RM: Cytoplasmic catalytic subunit of protein kinase A mediates cross-repression by NF-kappa B and the glucocorticoid receptor. Proc Natl Acad Sci USA 2000, 97:11893–8.View ArticlePubMedPubMed CentralGoogle Scholar
- Yang-Yen HF, Chambard JC, Sun YL, Smeal T, Schmidt TJ, Drouin J, Karin M: Transcriptional interference between c-Jun and the glucocorticoid receptor: mutual inhibition of DNA binding due to direct protein-protein interaction. Cell 1990, 62:1205–15.View ArticlePubMedGoogle Scholar
- Schule R, Rangarajan P, Kliewer S, Ransone LJ, Bolado J, Yang N, Verma IM, Evans RM: Functional antagonism between oncoprotein c-Jun and the glucocorticoid receptor. Cell 1990, 62:1217–26.View ArticlePubMedGoogle Scholar
- Brostjan C, Anrather J, Csizmadia V, Stroka D, Soares M, Bach FH, Winkler H: Glucocorticoid-mediated repression of NFkappaB activity in endothelial cells does not involve induction of IkappaBalpha synthesis. J Biol Chem 1996, 271:19612–6.View ArticlePubMedGoogle Scholar
- McKay LI, Cidlowski JA: Cross-talk between nuclear factor-kappa B and the steroid hormone receptors: mechanisms of mutual antagonism. Mol Endocrinol 1998, 12:45–56.View ArticlePubMedGoogle Scholar
- Jonat C, Rahmsdorf HJ, Park KK, Cato AC, Gebel S, Ponta H, Herrlich P: Antitumor promotion and antiinflammation: down-modulation of AP-1 (Fos/Jun) activity by glucocorticoid hormone. Cell 1990, 62:1189–204.View ArticlePubMedGoogle Scholar
- Kerppola TK, Luk D, Curran T: Fos is a preferential target of glucocorticoid receptor inhibition of AP-1 activity in vitro. Mol Cell Biol 1993, 13:3782–91.View ArticlePubMedPubMed CentralGoogle Scholar
- Nie M, Knox AJ, Pang L: beta2-Adrenoceptor agonists, like glucocorticoids, repress eotaxin gene transcription by selective inhibition of histone H4 acetylation. J Immunol 2005, 175:478–86.View ArticlePubMedGoogle Scholar
- Tliba O, Cidlowski JA, Amrani Y: CD38 expression is insensitive to steroid action in cells treated with tumor necrosis factor-alpha and interferon-gamma by a mechanism involving the up-regulation of the glucocorticoid receptor beta isoform. Mol Pharmacol 2006, 69:588–96.View ArticlePubMedGoogle Scholar
- Lenardo MJ, Baltimore D: NF-kappa B: a pleiotropic mediator of inducible and tissue-specific gene control. Cell 1989, 58:227–9.View ArticlePubMedGoogle Scholar
- Cousin E, Medcalf RL, Bergonzelli GE, Kruithof EK: Regulatory elements involved in constitutive and phorbol ester-inducible expression of the plasminogen activator inhibitor type 2 gene promoter. Nucleic Acids Res 1991, 19:3881–6.View ArticlePubMedPubMed CentralGoogle Scholar
- Lee W, Mitchell P, Tjian R: Purified transcription factor AP-1 interacts with TPA-inducible enhancer elements. Cell 1987, 49:741–52.View ArticlePubMedGoogle Scholar
- Lopez-Bayghen E, Vega A, Cadena A, Granados SE, Jave LF, Gariglio P, Alvarez-Salas LM: Transcriptional analysis of the 5'-noncoding region of the human involucrin gene. J Biol Chem 1996, 271:512–20.View ArticlePubMedGoogle Scholar
- Minta JO, Fung M, Turner S, Eren R, Zemach L, Rits M, Goldberger G: Cloning and characterization of the promoter for the human complement factor I (C3b/C4b inactivator) gene. Gene 1998, 208:17–24.View ArticlePubMedGoogle Scholar
- Risse G, Jooss K, Neuberg M, Bruller HJ, Muller R: Asymmetrical recognition of the palindromic AP1 binding site (TRE) by Fos protein complexes. EMBO J 1989, 8:3825–32.PubMedPubMed CentralGoogle Scholar
- Sweetser MT, Hoey T, Sun YL, Weaver WM, Price GA, Wilson CB: The roles of nuclear factor of activated T cells and ying-yang 1 in activation-induced expression of the interferon-gamma promoter in T cells. J Biol Chem 1998, 273:34775–83.View ArticlePubMedGoogle Scholar
- Beato M: Gene regulation by steroid hormones. Cell 1989, 56:335–44.View ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.