CD38 and airway hyper-responsiveness: studies on human airway smooth muscle cells and mouse models

Abstract

Asthma is an inflammatory disease in which altered calcium regulation, contractility, and airway smooth muscle (ASM) proliferation contribute to airway hyper-responsiveness and airway wall remodeling. The enzymatic activity of CD38, a cell-surface protein expressed in human ASM cells, generates calcium mobilizing second messenger molecules such as cyclic ADP-ribose. CD38 expression in human ASM cells is augmented by cytokines (e.g., TNF-α) that requires the activation of MAP kinases and the transcription factors, NF-κB and AP-1, and is post-transcriptionally regulated by miR-140-3p and miR-708 by binding to 3′ Untranslated Region of CD38 as well as by modulating the activation of signaling mechanisms involved in its regulation. Mice deficient in Cd38 exhibit reduced airway responsiveness to inhaled methacholine relative to the response in wild-type mice. Intranasal challenge of Cd38-deficient mice with TNF-α or IL-13, or the environmental fungus Alternaria alternata, causes significantly attenuated methacholine responsiveness compared with wild-type mice, with comparable airway inflammation. Reciprocal bone marrow transfer studies revealed partial restoration of airway hyper-responsiveness to inhaled methacholine in the Cd38-deficient mice. These studies provide evidence for CD38 involvement in the development of airway hyper-responsiveness; a hallmark feature of asthma. Future studies aimed at drug discovery and delivery targeting CD38 expression and (or) activity are warranted.

Full text

INVITED REVIEW
CD38 and airway hyper-responsiveness: studies on human
airway smooth muscle cells and mouse models
1
Alonso G.P. Guedes, Deepak A. Deshpande, Mythili Dileepan, Timothy F. Walseth,
Reynold A. Panettieri, Jr., Subbaya Subramanian, and Mathur S. Kannan
Abstract: Asthma is an inflammatory disease in which altered calcium regulation, contractility, and airway smooth muscle
(ASM) proliferation contribute to airway hyper-responsiveness and airway wall remodeling. The enzymatic activity of CD38, a
cell-surface protein expressed in human ASM cells, generates calcium mobilizing second messenger molecules such as cyclic
ADP-ribose. CD38 expression in human ASM cells is augmented by cytokines (e.g., TNF-␣) that requires the activation of MAP
kinases and the transcription factors, NF-␬B and AP-1, and is post-transcriptionally regulated by miR-140-3p and miR-708 by
binding to 3=Untranslated Region of CD38 as well as by modulating the activation of signaling mechanisms involved in its
regulation. Mice deficient in Cd38 exhibit reduced airway responsiveness to inhaled methacholine relative to the response in
wild-type mice. Intranasal challenge of Cd38-deficient mice with TNF-␣or IL-13, or the environmental fungus Alternaria alternata,
causes significantly attenuated methacholine responsiveness compared with wild-type mice, with comparable airway inflam-
mation. Reciprocal bone marrow transfer studies revealed partial restoration of airway hyper-responsiveness to inhaled meth-
acholine in the Cd38-deficient mice. These studies provide evidence for CD38 involvement in the development of airway
hyper-responsiveness; a hallmark feature of asthma. Future studies aimed at drug discovery and delivery targeting CD38
expression and (or) activity are warranted.
Key words: inflammatory cytokines, microRNAs, bone marrow chimeras, cyclic ADP-ribose.
Résumé : L'asthme est une maladie inflammatoire dans laquelle la régulation du calcium, la contractilité et la prolifération du
muscle lisse respiratoire (MLR) anormales contribuent a
`l'hyperréactivité bronchique et au remodelage des parois des voies
respiratoires. L'activité enzymatique du CD38, une protéine de la surface cellulaire exprimée par les cellules de MLR humains,
génère des seconds messagers qui mobilisent le calcium comme l'ADP-ribose cyclique. L'expression de CD38 par les cellules de
MLR est accrue par les cytokines (ex. TNF-␣), elle nécessite l'activation de MAP kinases et de facteurs de transcription comme
NF-␬B et AP-1, et elle est régulée au niveau post-transcriptionnel par miR-140-3p et miR-708 en liant la région 3=non transcrite de
CD38, de même qu'en modulant l'activation des mécanismes de signalisation impliqués dans sa régulation. La réponse respira-
toire a
`la méthacoline inhalée est réduite chez les souris déficientes en Cd38 comparativement aux souris sauvages. Une
provocation intra-nasale de souris déficientes en Cd38 avec du TNF-␣ou de l'IL-13, ou du champignon environnemental Alternaria
alternata, résulte en une réponse a
`la méthacoline atténuée comparativement aux souris sauvages, mais en une inflammation des
voies aériennes comparable. Des études de transfert réciproque de moelle osseuse ont révélé un rétablissement partiel de
l'hyperréactivité bronchique a
`la méthacoline inhalée chez les souris déficientes en Cd38. Cette étude présente des données qui
appuient l'implication du CD38 dans le développement de l'hyperréactivité bronchique, une caractéristique de l'asthme. Des
études futures visant le développement et la libération de médicaments ciblant l'expression et (ou) l'activité du CD38 sont
justifiées. [Traduit par la Rédaction]
Mots-clés : cytokines inflammatoires, micro ARN, moelle osseuse chimérique, ADP-ribose cyclique.
Introduction
CD38-cyclic ADP ribose (cADPR) signaling regulates a variety of
cellular/organ functions, and is known to play an important role
in diseases such as chronic lymphocytic leukemia (Malavasi et al.
2011). Studies from our laboratory established that (i) CD38 is ex-
pressed in airway smooth muscle (ASM) cells (White et al. 2000);
(ii) CD38–cADPR-mediated calcium release contributes to calcium
homeostasis in ASM cells (Deshpande et al. 2003); (iii) ASM con-
traction and bronchoconstriction are mediated, in part, by the
activation of the CD38–cADPR pathway. CD38 is also expressed on
the surface of immune cells, and is known to regulate immune
responses (Cockayne et al. 1998). Keeping in mind the physiologi-
cal role of CD38 in the regulation of ASM function, a key modula-
tor of airway tone, and immune cells, we hypothesized that the
CD38–cADPR signaling pathway regulates airway inflammation
and hyper-responsiveness (AHR). This review summarizes the
Received 20 October 2014. Accepted 25 November 2014.
A.G.P. Guedes. Department of Surgical & Radiological Sciences, University of California, Davis, CA 95616, USA.
D.A. Deshpande. Department of Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA.
M. Dileepan and M.S. Kannan. Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota,
1971 Commonwealth Avenue, St. Paul, MN 55108, USA.
T.F. Walseth. Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
R.A. Panettieri, Jr. Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
S. Subramanian. Department of Surgery, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
Corresponding author: Mathur S. Kannan (e-mail: kanna001@umn.edu).
1
This Invited Review is part of a Special Issue entitled “Smooth muscle and asthma: a tribute to Newman Stephens.”
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experimental data delineating the pathological roles of CD38 in
obstructive airway disease, asthma.
CD38: the enzyme responsible for cADPR synthesis
and degradation
Cyclic ADP-ribose (cADPR) is a calcium-releasing second messen-
ger derived from nicotinamide adenine dinucleotide (NAD). Results
from extensive biochemical studies have clearly demonstrated that
cADPR is synthesized by the action of ADP-ribosyl cyclase and de-
graded by cADPR hydrolase (Lee et al. 1999). The observation by Clap-
per et al. that the addition of NAD to sea urchin egg microsomes
results in calcium release from the microsomes led to the discovery
of cADPR (Clapper et al. 1987). There were a few key observations
made during this seminal study: (i) the addition of NAD to egg micro-
somes results in calcium release; (ii) the calcium release induced by
NAD is independent of inositol 1,4,5-trisphosphate (IP
3
); and (iii) the
kinetics of calcium release revealed a lag of 1–2 min after the addition
of NAD, suggesting the involvement of an enzymatic step that con-
verted NAD to a metabolite that was responsible for calcium mobili-
zation. Initial biochemical and biophysical studies and subsequent
X-ray crystallographic studies identified the cyclical nature of cADPR,
which is a calcium-releasing metabolite of NAD. ADP-ribosyl cyclase
was identified as the enzyme responsible for the conversion of NAD
to cADPR (Lee and Aarhus 1991). Originally, the NAD metabolizing
enzyme was purified from Aplysia ovotestis, but was named NADase
because methods to determine the intermediate products of NAD
metabolism were not available at the time (Hellmich and Strumwasser
1991). This ADP-ribosyl cyclase purified from Aplysia ovotestis is a
soluble protein of approximately 30 kDa (Lee and Aarhus 1991). Ini-
tial studies using various extracts obtained from mammalian tissues
revealed that the ADP-ribosyl cyclase activity is present in many tis-
sues (Rusinko and Lee 1989;Adebanjo et al. 2000). Subsequently, the
sequence comparison of the Aplysia cyclase (States et al. 1992) and
biochemical analysis revealed that CD38, a membrane-bound lym-
phocyte antigen, possesses ADP-ribosyl cyclase activity (Lee 2006)
and is considered the mammalian homolog of ADP-ribosyl cyclase
(Lee 2006). Interestingly, CD38 has both ADP-ribosyl cyclase and cADPR
hydrolase activities (Fig. 1). It is ⬃45 kDa in size and found associated
with the cell membrane. Subsequent studies demonstrated that
ADP-ribosyl cyclase and cADPR hydrolase activities are also associ-
ated with other membrane-bound proteins such as bone marrow
stromal cell surface antigen (BST)-1 or CD157, in mammals
(Yamamoto-Katayama et al. 2001). BST-1 was identified as homolo-
gous to CD38.
Studies using human, murine, and porcine ASM confirmed the
expression of CD38 and the enzyme activities associated with
CD38 in ASM (Deshpande et al. 2005a). CD38 is the primary source
for cADPR production in ASM, although non-CD38 ADP-ribosyl
activities have also been described in other cell types (Ceni et al.
2006). siRNA-mediated knockdown or genetic ablation of CD38
results in diminished levels of cADPR (Kang et al. 2005) and
increase in CD38 expression results in increased levels of cADPR in
ASM (Deshpande et al. 2003) demonstrating a role of CD38 in
mediating cADPR production. In ASM, cells obtained from Cd38
knockout (KO) mice, a low level of cADPR is detectable in ASM,
suggesting a potential source of non-CD38 ADP-ribosyl cyclases in
ASM (Deshpande et al. 2005b). Interestingly, agonist stimulation
seems to favor cADPR synthesis in ASM cells. Further studies are
needed to establish the time kinetics of cADPR synthesis and deg-
radation in ASM cells.
In addition to the activities that enable CD38 to produce cADPR
(ADP-ribosyl cyclase) and degrade cADPR (cADPR hydrolase), this
enzyme has been shown to produce 2 other metabolites that are
involved in the regulation of calcium homeostasis. CD38 hy-
drolyzes NAD to cADPR (Zocchi et al. 1993), and synthesizes nico-
tinic acid adenine dinucleotide phosphate (NAADP) from NADP
and nicotinic acid via a base-exchange reaction (Aarhus et al. 1995).
cADPR and NAADP have been shown to play important roles in
calcium signaling. cADPR regulates calcium influx via transient re-
ceptor potential cation channel, subfamily M, member 2 (TRPM2)
channels (Perraud et al. 2001), whereas NAADP regulates calcium
release from acidic endolysosomal stores through regulation of 2
pore channels (Calcraft et al. 2009). NAADP was shown to contribute
to acetylcholine-induced contraction of guinea pig trachea and
oxytocin-induced contraction of rat uterine smooth muscle (Aley
et al. 2010,2013). Thus, CD38 produces 2 second messengers, cADPR
and NAADP, which regulate calcium release and contractility in
ASM.
cADPR and regulation of ASM calcium homeostasis
and contraction
Calcium homeostasis in ASM is regulated by a complex inter-
play of second messenger molecules, ion channels, signaling reg-
ulatory molecules, and calcium stores. This includes calcium
influx–efflux mechanisms and release/re-uptake processes. NAD
metabolites cADPR and NAADP have emerged as calcium-releasing
second messengers, and presumably mediate calcium release
through ryanodine receptor (RyR) channels (Albrieux et al. 1998;
Lee 2011). We and other airway biology investigators have clearly
demonstrated the contribution of cADPR-mediated calcium release
in ASM, using both pharmacological and genetic approaches. The
conclusion stems from a series of experiments carried out using
freshly isolated porcine ASM cells, cultured primary human ASM
cells, and murine ASM cells obtained from wild type (WT) and Cd38
KO mice. The following observations support this interpretation:
(i) pre-incubation of ASM cells with 8-bromo-cADPR (a cell perme-
able cADPR antagonist) inhibits agonist-induced intracellular cal-
cium ([Ca
2+
]
i
) responses in human ASM cells (Prakash et al. 1998;
White et al. 2003); (ii) the addition of extracellular cADPR to por-
cine/bovine ASM cells causes concentration-dependent increases
in [Ca
2+
]
i
(Franco et al. 2001); (iii) up-regulation of CD38 by overex-
pression or cytokine treatment results in enhanced calcium re-
sponses to G-protein-coupled receptor (GPCR) agonists (Prakash
et al. 1998); (iv) down-regulation of CD38 expression by anti-sense
CD38 expression attenuates agonist-induced calcium responses in
ASM cells (Kang et al. 2005); (v) calcium responses to acetylcholine
or endothelin are significantly diminished in ASM cells obtained
from Cd38 KO mice compared with WT mice (Deshpande et al.
2005b); (vi) the addition of cADPR to equine tracheal smooth mus-
cle cells results in increased amplitude and frequency of sponta-
neous transient inward currents (STICs), suggesting spontaneous
release of calcium by cADPR in ASM cells (Wang et al. 2004); and
(vii) siRNA-mediated downregulation of CD38 expression attenu-
ates cytokine-induced increase in store-operated calcium entry in
ASM cells (Sieck et al. 2008).
cADPR-mediated calcium release is believed to involve the acti-
vation of RyR channels on the sarcoplasmic reticulum (SR). Phar-
macological and biochemical approaches employed in ASM cells
confirmed the role of RyRs in effecting calcium release by cADPR
(Deshpande et al. 2005a). Several lines of evidence exist in this
regard: (i) calcium release by cADPR is not sensitive to pretreat-
ment with IP
3
R antagonist, and (ii) inhibitors of RyR channels
(ryanodine, ruthenium red, procaine, and Mg
2+
) inhibit cADPR-
mediated calcium release. However, RyRs do not possess binding
pockets for cADPR, although high-affinity binding of
32
P-cADPR to
permeabilized smooth muscle cells and tissue lysates provide the
experimental evidence for cADPR–SR interaction. The interaction
of cADPR and RyR may involve additional accessory proteins such
as calmodulin and FK506-binding protein (Wang et al. 2004).
These results indicate that cADPR mediates calcium release via
RyR, either directly or indirectly via accessory proteins.
Calcium elevation in ASM has a causal relationship with con-
traction. The role of CD38–cADPR in mediating contraction has
been investigated in the smooth muscle of intestine, seminiferous
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tubules, blood vessels, trachea, and uterus. In longitudinal smooth
muscles of intestine, cADPR elicited contractions in a concentration-
dependent manner (Kuemmerle and Makhlouf 1995;Kuemmerle
et al. 1998). This was the first study to demonstrate the contractile
response induced by cADPR. Similarly, application of cADPR or
3-deaza cADPR, a non-hydrolyzable cADPR analog, increased acetyl-
choline-induced contractions of smooth muscle strips isolated
from bovine trachea, and pre-incubation of the ASM strips with
8-amino cADPR, a cADPR antagonist, attenuated this response
(Franco et al. 2001). Murine tracheal ring contractility ex vivo in
WT and Cd38 KO mice is not significantly different under naïve
conditions. However, the in-vivo airway responsiveness to differ-
ent doses of inhaled methacholine, as determined by changes in
lung resistance and dynamic compliance, are significantly lower
in Cd38 KO mice compared with WT controls (Deshpande et al.
2005b;Guedes et al. 2006,2008). This evidence clearly demon-
strates the functional role of CD38–cADPR in the regulation of
ASM contractility and in vivo lung function (Fig. 1).
In summary, studies in ASM have clearly demonstrated the role
of cADPR-mediated calcium release in the regulation of calcium
homeostasis. Further, CD38 is the primary (if not the only) cADPR-
generating membrane-bound bi-functional enzyme in ASM. It
must be expected that any change in the expression or activity of
CD38, the enzyme responsible for cADPR metabolism, would re-
sult in augmented calcium release in effector cells, namely, ASM
cells (Fig. 1).
cADPR and airway hyper-responsiveness
Asthma is an inflammatory disease in which pro-inflammatory
cytokines have a role in inducing abnormal ASM function and in
the development of AHR. Inflammatory cytokines alter Ca
2+
sig-
naling and the contractility of ASM, which results in nonspecific
hyper-reactivity to agonists (Deshpande et al. 2003,2004,2005a).
We explored whether CD38–cADPR-mediated calcium release in
ASM is altered under inflammatory conditions, and contributes to
AHR. Altered expression and function of CD38 have been demon-
strated in pathological conditions such as diabetes (Okamoto et al.
1997), hypoxia-induced vascoconstriction (Wilson et al. 2001), and
hematopoietic malignancies (Malavasi et al. 2011). Several lines of
evidence have suggested a role for CD38–cADPR in AHR: (i) pre-
treatment of ASM cells with different concentrations of inflamma-
tory (tumor necrosis factor (TNF)-␣, interleukin (IL)-1␤, interferon
(IFN)-␥) or T helper type 2 lymphocyte (TH2) (IL-13) cytokines results
in increased CD38 expression and cADPR production (Deshpande
et al. 2003,2004); (ii) augmented calcium responses to different
GPCR agonists (indicating AHR) can be attenuated with a cell-
permeable cADPR antagonist (White et al. 2003); (iii) the augmenta-
tion of CD38 expression and therefore the capacity for CD38–cADPR
signaling is significantly greater following TNF-␣exposure in ASM
cells derived from asthmatics than in cells from non-asthmatics
(Jude et al. 2010); (iv) siRNA-mediated knockdown of CD38 expression
inhibits TNF-␣-induced augmented store-operated calcium entry (an-
other indicator of AHR) in ASM (Sieck et al. 2008); (v) ex-vivo treat-
ment of tracheal rings with IL-13 results in an increased contractility
to carbachol exposure in WT mice but not in Cd38 KO mice (Guedes
et al. 2008); (vi) glucocorticoids (drug of choice in asthma treatment)
inhibit cytokine-induced CD38 expression (Kang et al. 2008) and
cADPR-mediated calcium release (D.A. Deshpande and M.S. Kannan,
unpublished observation) in human ASM cells. These studies collec-
tively demonstrate a causal relationship among CD38 expression,
cADPR production, and agonist-induced calcium elevation and ASM
contraction, which are altered under inflammatory conditions.
CD38 gene organization and regulation of
expression
Regulating the expression of CD38 is a potential drug target to
mitigate inflammation-induced AHR. In this context, understand-
ing the molecular mechanisms involved in CD38 expression is a
Fig. 1. Synthesis and degradation of cADPR by CD38. ␤-NAD is converted into cADPR by ADP-ribosyl cyclase and hydrolyzed by cADPR
hydrolase; both enzyme activities are associated with a single transmembrane protein, CD38 in mammals. CD38 expressed on immune cells
contributes to humoral and cell-mediated immunity, whereas CD38 on airway smooth muscle (ASM) cells, by releasing cADPR, regulates
calcium homeostasis, contraction, and bronchoconstriction. Important to note is that increase in expression of CD38 (dotted arrows) results
in an altered calcium homeostasis, hyper-contractility of ASM, and airway hyper-responsiveness.
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logical and critical first step. Studies from our laboratory have
shed light on transcriptional and post-transcriptional regulation
of CD38 expression in human ASM cells.
Sequence analysis ofa3kbputative CD38 promoter fragment
(GenBank accession No. DQ091293) cloned from a human eryth-
ropoietic cell line (K562 cells) in our laboratory revealed binding
sites for nuclear factor kappa-light-chain-enhancer of activated B
cells (NF-␬B), activator protein 1 (AP-1), and glucocorticoid receptor
(Tirumurugaan et al. 2008)(Fig. 2). There is one NF-␬B, 6 AP-1, and
4 glucocorticoid response element (GRE) binding motifs in the
CD38 gene. Electrophoretic mobility shift assay (EMSA) confirmed
direct binding of NF-␬B and AP-1 to putative binding sites on CD38
promoter. The AP1–4 site (residing between –2798 to –2789 bp)
that shows very strong binding in EMSA studies was found to be
functionally important, since mutation of this site profoundly
affected TNF-␣-induced activation of CD38 expression.
The CD38 gene (>80 kb long), comprising 8 exons, is located on
chromosome 4 in the human genome and chromosome 5 in the
mouse genome (Ferrero et al. 2000). Binding sites for several
transcription-activating factors in the CD38 gene have been iden-
tified (Ferrero et al. 2000). Previous studies have shown the ab-
sence of a canonical TATA or CAAT box sequences in the CD38
promoter region, suggesting that transcription can be initiated at
multiple sites (Ferrero et al. 2000). 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. Other additional con-
sensus binding sites for T cell transcription factor (TCF-1␣), Ig gene
box enhancer motifs (␮E1, ␮E5, and ␬E2), NF-IL6, and IFN-responsive
factor-1 have been identified in the CD38 5=Untranslated Region (UTR)
region. Interestingly, the DR5 repeat (TGACCCgaaagTGCCCC) se-
quence was identified within intron 1, which has a role in retinoic
acid induction of CD38 expression in HL-60 cells (Mehta and
Cheema 1999). A CpG island of ⬃900 bp length was identified in
the CD38 gene 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 (Sun et al. 2006). Furthermore,
a glucocorticoid response element and an estrogen binding mo-
tif have also been described in the promoter region of CD38
(Tirumurugaan et al. 2008). Taken together, it is likely that the
transcriptional regulation of CD38 expression by cytokines, gluco-
corticoids, and hormones may have a physiological and patho-
physiological role in the regulation of lung functions and
pulmonary diseases.
Inflammatory cytokines such as TNF-␣, IL-1␤, and IFN-␥play an
important role in diseases such as asthma (ten Hacken et al. 1998;
Lappalainen et al. 2005;Berry et al. 2007). TNF-␣has been shown to
increase the expression of a variety of genes, resulting in func-
tional changes in ASM cells (Alrashdan et al. 2012). Studies from
our laboratory and others have demonstrated that TNF-␣upregu-
lates CD38 expression in ASM. TNF-␣induced change in CD38
expression in human ASM cells involves NF-␬B and AP-1 activa-
tion, and signaling through the p38 and JNK MAP kinases
(Tirumurugaan et al. 2007). Sequence analysis of the cloned hu-
man CD38 promoter also reveals 4 putative binding sites for the
transcription factor c/EBP␤, 3 of which are within a region up-
stream of the NF-␬B site. TNF-␣via TNFR1 receptor induces CD38
expression in ASM cells in an IFN␤-dependent manner (Tliba et al.
2004).
Inflammatory cytokines activate multiple signaling pathways,
ultimately resulting in the transcriptional activation of various
genes. The studies described above clearly demonstrate that cyto-
kines via upstream signal activation regulate CD38 expression by
multiple transcription factors. This knowledge provides a frame-
work for developing therapeutic strategies aimed at containing
CD38 expression induced by inflammatory mediators and hor-
mones.
CD38 expression: findings from asthmatic
ASM cells
ASM obtained from asthmatics is different from smooth muscle
obtained from healthy subjects in terms of expression and activity
Fig. 2. Organization of the CD38 gene and potential regulatory sites. Genomic analysis of the CD38 gene reveals the presence of several
transcription factor binding sites upstream of ATG. Inflammatory cytokines such as TNF-␣through the MAP kinase pathway activate
transcription factors and regulate CD38 expression. Full-length CD38 mRNA has binding sites for several microRNAs, suggesting potential
post-transcriptional regulation of CD38 expression (Dileepan et al. 2014). Transfection of airway smooth muscle (ASM) cells with miR-140-3p
causes decreased p38 MAP kinase and NF-␬B activation and CD38 expression. Transfection of ASM cells with miR-708-5p causes decreased JNK
MAP kinase activation, increased expression of the MAP kinase phosphatase MKP-1, and PTEN that regulates PI3K–AKT signaling and
CD38 expression. Solid lines represent increased expression/activation of proteins; broken lines represent the inhibition of
expression/activation. GRE, glucocorticoid response element; c/EBP, CCAAT/enhancer binding protein.
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of different signaling molecules and contractile apparatus. Stud-
ies of gene expression in airway biopsies from mild allergic asth-
matics and non-asthmatics reveal increased expression of fast
myosin heavy chain isoform, transgelin, and myosin light-chain
kinase (MLCK) in tissues from asthmatics, reflecting faster velocity
of actin filament propulsion and AHR (Leguillette et al. 2009).
Increased phospho-ERK1/2 and p38 MAPKs, with augmented ex-
pression of ERK1/2-inducible proteins sprout-2 and JunB were
noted in the airways of asthmatics (Liu et al. 2008). JunB is a
transcription factor that is part of the AP-1 complex and is in-
volved in ERK1/2-mediated transcriptional regulation in the air-
ways (Reddy and Mossman 2002). Increased expression of CD40
and OX40 ligand, cell-surface molecules involved in immuno-
modulatory functions of ASM cells (Krimmer et al. 2009), have
been reported from biopsy specimens. Reports support an in-
creased rate of cell proliferation resistant to glucocorticoids, ca-
pacity to develop force, and secretion of chemokines in ASM cells
obtained from asthmatics compared with cells from healthy sub-
jects (Ma et al. 2002;Damera et al. 2009;Prefontaine et al. 2009).
These reports indicate a definite asthmatic phenotype of asth-
matic ASM cells, characterized by differential expression of genes
involved in contractility, MAP kinase signaling, cell-to-cell and
cell-to-matrix interactions, transcription factors, and chemokines
involved in the recruitment of inflammatory cells into the airways
during allergic airway disease.
A systematic study delineating the expression of CD38 in ASM
obtained from asthmatics and non-asthmatics is lacking. How-
ever, in asthmatic ASM cells maintained in culture, we did not
find any change in the constitutive expression of CD38 compared
with ASM cells obtained from healthy donors. Interestingly, a
comparison of CD38 expression induced by TNF-␣between ASM
cells obtained from asthmatics and non-asthmatics revealed that
asthmatic ASM cells are capable of significantly greater levels of
expression than non-asthmatic ASM cells (Jude et al. 2010). There
was greater sensitivity to TNF-␣for CD38 expression in asthmatic
ASM cells than in non-asthmatic ASM cells. This differential in-
duction of CD38 expression by inflammatory cytokines appears
not to be associated with altered activation of the transcription
factors NF-␬B and AP-1 or with altered transcript stability. Further-
more, the differential induction of CD38 expression was associ-
ated with decreased JNK MAP kinase activation and increased
activation of ERK and p38 MAP kinases. These observations indi-
cated the combined role of transcription factors, increased rate of
transcription, and translational regulation in effecting differen-
tial induction of CD38 in asthmatic cells. In this context, we in-
vestigated post-transcriptional mechanisms in the regulation of
CD38 expression in ASM cells derived from asthmatic and non-
asthmatic donor lungs.
CD38 expression: regulation by post-transcriptional
mechanisms
MicroRNAs (miRNAs) are a group of small non-coding RNAs that
post-transcriptionally regulate gene expression (Bartel 2004;He
and Hannon 2004;Ha and Kim 2014). The biogenesis of miRNAs is
a complex process. RNA polymerase II (RNA Pol II), or less fre-
quently Pol III, generates a primary miRNA transcript (pri-miRNA),
which is then exported to the cytoplasm by exportin-5. Here, it is
further processed to form precursor miRNAs (pre-miRNA). Dicer,
an RNAse III enzyme, along with its co-factors cleaves the terminal
loop from the pre-miRNA to generate miRNA duplex. One of the
2 strands form mature miRNA (18–23 nucleotides) that generally
becomes the guide strand that is incorporated into a ribonucle-
otide complex to form miRISC (miRNA-induced silencing com-
plex). Based on the complementarities between the guide miRNA
and the target mRNA, miRNA can either cleave target RNAs with
the help of Ago2, or induce a translational suppression. miRNA-
mediated gene regulation is crucial in the biological system, as
they can regulate hundreds of different mRNAs that play essential
roles in various cellular functions. Therefore, any alteration of
miRNA expression can result in various human disease conditions
(Subramanian and Kartha 2012; sarcomas), including asthma.
Recent reports have demonstrated that the expression of sev-
eral miRNAs is down-regulated by inflammatory cytokines in hu-
man ASM cells (Chiba et al. 2009;Kuhn et al. 2010;Jude et al.
2012a). There is evidence for control of ASM contractility and re-
laxation (Chiba et al. 2009;Wang et al. 2011), ASM phenotype (Hu
et al. 2014;Kuhn et al. 2010), and ASM proliferation (Hu et al. 2014)
by specific miRNAs. A recent report showed that miR-10a regu-
lates ASM cell proliferation by a mechanism that involves the
suppression of the expression of the catalytic subunit of PI3 ki-
nase, leading to decreased AKT phosphorylation (Hu et al. 2014). It
is worth noting that the PI3 kinase–AKT signaling contributes to
the hyperproliferative phenotype of asthmatic ASM cells (Burgess
et al. 2008). Furthermore any role for CD38–cADPR signaling in
the regulation of ASM growth and proliferation has not been in-
vestigated. Based on the pleiotropic role of this signaling pathway,
we predict that CD38 promotes ASM growth. Further, it is imper-
ative to emphasize the importance of miRNA in the regulation of
expression and activity of numerous intracellular signaling mol-
ecules, including CD38, in ASM thereby contributing to AHR.
We used multiple web-based target prediction algorithms to
determine potential miRNA targets in the CD38 3=UTR (Dileepan
et al. 2014). We found that miRNAs miR-1272, miR-548, miR-208a,
miR-1298, miR-708, and miR-140-3p were predicted to bind to the
CD38 3=UTR with a high context score. Initial exploratory studies
revealed the following: (i) human ASM cells express miR-708 and
miR-140-3p at a relatively higher level compared with the expres-
sion of other miRNAs; (ii) the expression of miR-708 and miR-
140-3p is regulated by treatment with TNF-␣; and (iii) asthmatic
and non-asthmatic ASM cells demonstrate different sensitivity to
cytokine-induced expression of miR-708 and miR-140-3p (Dileepan
et al. 2014;Jude et al. 2012a). The expression of miR-140-3p was
found to be lower and reduced to a greater extent by TNF-␣in ASM
cells from asthmatics compared with levels in cells from non-
asthmatics. However, miR-708 expression was found to be re-
duced by TNF-␣in non-asthmatic ASM cells compared with the
expression in vehicle-treated cells, whereas it caused an increase
in miR-708 expression in ASM cells from asthmatics (Dileepan
et al. 2014). We hypothesized that dysregulation of the expression
of these 2 miRNAs is involved in the augmented cytokine-induced
CD38 expression in human ASM cells. The mechanisms by which
these 2 miRNAs regulate the expression of CD38 were also deter-
mined in these studies.
miRNAs inhibit gene expression directly by binding to the tar-
get gene at the 3=UTR, or indirectly by inhibiting other signaling
pathways (Dileepan et al. 2014;Jude et al. 2012a). We carried out
CD38 3=UTR-luciferase reporter assays to determine whether there
is evidence for the control of CD38 expression by direct binding.
Our results revealed that regulation of CD38 expression by miR-
708 and miR-140-3p results from binding to 3=-UTR of CD38. How-
ever, this binding did not have any effect on CD38 transcript
stability, suggesting that translational repression may be an un-
derlying mechanism for regulation. We also evaluated the effects
of these 2 miRNAs on the signaling mechanisms and transcription
factors involved in the regulation of CD38 expression in human
ASM cells. Prior investigations in the laboratory have demonstrated
that CD38 expression is regulated by p38 and JNK MAP kinases at the
transcriptional level, whereas ERK and p38 MAP kinase regulation
involved post-transcriptional mechanisms (Tirumurugaan et al.
2007). Furthermore, specific isoforms of the PI3 kinases (Jude et al.
2012b) and the transcription factors NF-␬B and AP-1 are critical in
this regulation (Tirumurugaan et al. 2007). The evidence for this
came from the use of isoform-specific pharmacological inhibitors
of the catalytic subunit of PI3 kinase, transfection of cells with
dominant negative constructs for the transcription factors, and
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Guedes et al. 5
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deletion of the binding sites for the transcription factors
(Tirumurugaan et al. 2007). Transfection of human ASM cells with
miR-140-3p mimic oligonucleotides revealed down-regulation of
p38 MAP kinase and NF-␬B activation (Jude et al. 2012a). On the
other hand, transfection of cells with miR-708 mimic oligonucle-
otides caused down-regulation of JNK MAP kinase activation, with
no significant change in the expression of total JNK MAP kinase
(Dileepan et al. 2014). In addition, miR-708 transfection of the cells
caused up-regulation of phosphatase and tensin homolog (PTEN),
which regulates PI3 kinase signaling through the activation of
AKT and a dual-specificity phosphatase, also known as MAP kinase
phosphatase-1 (DUSP-1 or MKP-1) that regulates MAP kinase signal-
ing (Fig. 2; see also Dileepan et al. 2014). These findings indicated
that miR-140-3p regulation of CD38 expression stems from altered
p38 MAP kinase and NF-␬B activation, whereas regulation by miR-
708 stems from altered PI3 kinase–AKT signaling and JNK MAP
kinase activation. The combined effect on PTEN and DUSP-1 induc-
tion by miR-708 should have a profound effect on the 2 signaling
pathways involved in the inflammation and cell proliferation.
Airway remodeling is another key component of asthma, and
future studies should focus on assessing the role of CD38 in the
regulation of ASM growth.
These new findings support the concept that the capacity for
CD38 signaling in the asthmatic airways is significantly higher
than in the airways of healthy subjects. These findings have a
significant impact in terms of the role of CD38 in asthma and
understanding the regulation of CD38 expression and function in
the asthmatic airways may help identify novel therapeutic tar-
gets. The miRNAs that were investigated in the abovementioned
studies target different signaling mechanisms involved in the reg-
ulation of CD38 expression and may provide another therapeutic
strategy in inflammatory airway diseases such as asthma and
chronic obstructive pulmonary disease (COPD).
Airway inflammation and hyper-responsiveness
Airway hyper-responsiveness to contractile agonists is a key
feature of asthma; a chronic inflammatory disease of the airways
that results from a complex interplay between genetic and envi-
ronmental factors (Chen et al. 2003;Factor 2003;O'Byrne and
Inman 2003;Fredberg 2004). In asthma, inhaled allergens are
taken up by airway dendritic cells, which subsequently migrate to
bronchial lymph nodes where they mature into immunostimula-
tory cells capable of efficiently presenting antigen to T-helper
(CD4
+
) cell precursors. The cytokine balance in the lymph node
determines the fate of these precursor cells. If IL-12 predominates,
then precursor cells become type 1 T-helper cells (Th1) that pro-
duce IFN-␥, IL-2, TNF-␣, and lymphotoxin, collectively referred to
as Th1 cytokines. Conversely, if IL-4 predominates in the node,
CD4
+
precursor cells become type 2 T-helper cells (Th2), which
secrete the Th2 cytokines IL-4, IL-5, IL-9, and IL-13. These Th2 cyto-
kines, among other mediators, recruit eosinophils to the airways.
Binding and antigen-dependent cross-linking of IgE-bound high
affinity receptors (Fc3RI) on eosinophils and resident mast cells
results in the activation and degranulation with local release of
mediators that cause airway injury, increased mucous produc-
tion, and the development of AHR (Factor 2003;Komai et al. 2003;
Cohn et al. 2004;Robinson 2004;Williams 2004). Once a Th2-type
response has occurred, Th2 memory cells alone appear to deter-
mine the development of AHR and pulmonary eosinophilia to
antigen challenge in a manner that is refractory to inhibition by
Th1 cells or endogenous inhibitory mechanisms (Aronica et al.
2004). However, the effects of Th1 responses on Th2 response-
induced lung injury seem to be ambiguous, since the Th1 cytokine
IFN-␥was shown to be concomitantly inhibitory and stimulatory
on the effects of the Th2 cytokine IL-13 in a mouse model of lung
inflammation (Ford et al. 2001). Furthermore, airway exposure to
TNF-␣, a Th1 cytokine, can cause substantial AHR and inflamma-
tion (Thomas et al. 1995;Thomas and Heywood 2002;Guedes et al.
2008).
Inflammatory cells (i.e., lymphocytes, mast cells, eosinophils)
and inflammatory mediators (i.e., cytokines, eicosanoids) interact
with ASM, inducing important anatomic and functional changes
(Webb et al. 2000;Tliba et al. 2003;Tliba and Panettieri 2008;
Damera and Panettieri 2011). After repeated exposure to allergens,
the ASM may continue to proliferate even after resolution of the
inflammatory process (Leung et al. 2004). Therefore, while airway
wall swelling and airway plugging by excessive secretion are im-
portant amplifying factors, the major end-effector of acute airway
narrowing in asthma is the ASM (FitzGerald and Macklem 1996;
Fredberg 2004).
Collectively these studies suggest that the pathogenesis of
asthma involves a 2-step process: (i) inflammation, and (ii) cellular
changes leading to functional abnormalities (e.g., AHR). Interest-
ingly, CD38 is expressed on immune cells as well as resident air-
way cells, including ASM cells. Predictably, CD38 plays a pivotal
role both in the onset of allergen-induced inflammatory response
and AHR (Fig. 1). Studies on integrative models using Cd38 KO mice
have provided insights into multiple roles of CD38–cADPR signal-
ing in the pathogenesis of asthma (Table 1).
CD38 in airway inflammation and AHR: findings
from mouse models of asthma
Naïve Cd38 KO mice exhibit very low cADPR levels in the lungs,
attenuated [Ca
2+
]
i
responses to spasmogens such as endothelin-1
and acetylcholine in ASM, and decreased airway responsiveness to
inhaled methacholine compared with their WT counterparts
(Deshpande et al. 2005b;Guedes et al. 2006,2008). Cytokine-
induced changes in CD38–cADPR signaling have also been inves-
tigated using mouse models of airway inflammation and AHR
(Guedes et al. 2006,2008). Intranasal challenge with the Th2 cyto-
kine IL-13 or with the pro-inflammatory cytokine TNF-␣caused
significantly lower AHR to inhaled methacholine in the Cd38 KO
mice compared with the WT controls, but a robust and compara-
ble airway inflammation was elicited in both groups of mice. Iso-
metric force generation of tracheal segments incubated with IL-13
or TNF-␣is also significantly lower in the Cd38 KO mice compared
with the WT controls (Guedes et al. 2006,2008). Together with the
demonstrated role of CD38–cADPR signaling in calcium homeo-
stasis in ASM cells under naïve conditions and after cytokine treat-
ment, these studies suggest the contribution of this signaling
system to ASM contractility under normal and inflammatory con-
ditions.
Table 1. Studies on integrative models using Cd38 knockout (KO)
mice.
WT Cd38 KO References
Naïve mice Deshpande et al. 2005b
Inflammation 0 0
Airway responsiveness + –
IL-13 challenge Guedes et al. 2008
Inflammation ++++ ++++
Airway responsiveness ++++ ++
TNF-␣challenge Guedes et al. 2006
Inflammation 0 0
Airway responsiveness ++++ ++
Fungal antigen challenge Guedes et al. 2006
Inflammation ++++ ++++
Airway responsiveness ++++ +
Ovalbumin challenge Gally et al. 2009
Inflammation +++ ++
Airway responsiveness ++ +
Note: WT, wild type; 0, unchanged response compared with the naïve mice;
–, decreased response compared with the naïve mice; ++++, maximal response
compared with the naïve mice.
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6 Can. J. Physiol. Pharmacol. Vol. 93, 2015
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The CD38–cADPR–Ca
2+
signaling system also plays a role in the
regulation of humoral immune responses in vivo by directing
dendritic cells chemotaxis, antigen presentation, and adequate
T cell priming as shown in studies using Cd38 KO mice (Cockayne
et al. 1998;Partida-Sanchez et al. 2004a,2004b). Furthermore,
CD38 ligation with agonist monoclonal antibodies (mAb) or its
natural ligand CD31 in peripheral blood T cells and monocytes
induces the expression and secretion of a mixed Th1- (IFN-␥, IL-2)
and Th2-type (IL-6, IL-10) cytokine profile (Ausiello et al. 1996;
Deaglio et al. 1998;Lande et al. 2002). Since airway inflammation
is a hallmark of asthma, the above observations suggest that the
CD38–cADPR signaling, specifically in immune cells, may have a
role in the pathophysiology of allergic airway diseases.
There is strong evidence from independent studies using mouse
models that CD38 is involved in airway inflammation and AHR
(Guedes et al. 2006,2008;Gally et al. 2009). However, whether or
not the involvement of CD38 in asthma pathogenesis is primarily
due to its role in inflammatory or resident lung cells has not been
fully resolved. A recent study using a mouse model of ovalbumin-
induced airway inflammation and AHR showed that Cd38 KO mice
did not develop inflammation or eosinophilia in the lungs, had
consistently lower levels of IL-4, IL-5, and IL-13 in culture super-
natants of peribronchial lymph nodes, and had reduced AHR
compared with the controls (Table 1). Reciprocal bone-marrow
transfer experiments indicated that CD38 acts both as a modula-
tor of the immune response and plays an equally important role
as an intrinsic pulmonary component (Gally et al. 2009). However,
intranasal challenge with an extract of the environmental fungus
Alternaria alternata, an epidemiologically relevant allergen, caused
pronounced and equivalent increases in eosinophil numbers and
IL-13 concentrations in bronchoalveolar lavage fluid in Cd38 KO
and WT mice, but AHR was significantly lower in the Cd38 KO
mice (Guedes et al. 2006). Transferring CD38 KO bone marrow into
WT mice or vice-versa does not alter the typical responses seen in
intact mice challenged with IL-13. In other words, WT bone mar-
row transferred into CD38 KO recipients does not restore AHR to
the WT levels. Similarly, transfer of Cd38 KO bone marrow into
WT mice does not diminish their AHR to the levels seen in the
Cd38 KO mice. Furthermore, airway inflammation in WT and Cd38
KO mice following reciprocal bone marrow transfer and IL-13 chal-
lenge is similar. Hence, reciprocal bone marrow transfer does not
alter their typical inflammatory and methacholine responses
(A.G. Gueddes and M.S. Kannan, unpublished results). These re-
sults argue in favor of a hypothesis that CD38 expression in lung
structural cells is the primary determinant of AHR in the fungal-
and cytokine-induced asthma in murine models. It would be in-
teresting to determine the structural changes (e.g., ASM mass) in
the Cd38 KO by comparison with the WT lungs after allergen
challenge or cytokine treatment.
Conclusions and future directions
Studies from human ASM cells (asthmatic and non-asthmatic)
and murine models of asthma have clearly demonstrated the role
of CD38–cADPR-mediated signaling in the regulation of airway
function, inflammation, and hyper-responsiveness. Can CD38
serve as a potential anti-asthma target? Basic and pre-clinical stud-
ies strongly support this notion. Regulation of CD38 expression or
activity could mitigate the severity of allergen-induced airway
inflammatory diseases. The challenge lies in the development of
pharmacological tools to inhibit the enzyme (ADP-ribosyl cyclase)
activity associated with CD38. Advanced medicinal chemistry ap-
proaches and computer assisted drug design tools may assist in
developing inhibitors of ADP-ribosyl cyclase. Delivering drugs to
inhibit CD38 function in ASM or immune cells could be achieved
through the use of nanotechnology. Recent studies have demon-
strated the use of nanoparticle technology to augment the drug
delivery effectively. The concept of one-bead-one-compound com-
binatorial chemistry to discover ligands against several different
cell surface integrins has gained momentum in recent years. One
of these ligands, LLP2A (a high-affinity peptidomimetic antagonist
against activated ␣4␤1 integrin), was found to bind strongly to
human airway fibroblasts (HAF) leaving other cell types intact.
This approach could be used for targeted delivery of novel drugs
to specific resident airway cells. miRNAs seem an additional at-
tractive target; however, the off-target effects of miRNA pose a
major challenge. Future studies using new bioinformatics tools
may offer a much required solution by establishing the specificity
for miRNAs in the regulation of CD38 expression.
Acknowledgements
The authors wish to thank Dr. J.A. Jude, Dr. B.N. Kang,
Dr. K.G. Tirumurugaan, and Dr. T.A. White whose work has been
cited in this review. The investigations from the laboratory cited
in this review have been supported by grants from the National
Institutes of Health, Academic Health Center, University of Min-
nesota, and the Comparative Medicine Research Program, College
of Veterinary Medicine, University of Minnesota.
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