Histamine downregulates aquaporin 5 in human nasal

epithelial cells
Weiwei Wang, M.D.,1 Xiaolian Wang, M.M.,2 Lan Ma, M.M.,2 and Ruitao Zhang, M.D.,2

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ABSTRACT
Background: Aquaporin 5 (AQP5) is a water-specific channel protein. It is thought to be a key participant in fluid secretion and a rate-limiting barrier to the
secretion seen during allergic inflammation. We sought to determine the effect of histamine on AQP5 expression in human nasal epithelial cells (HNEpC).

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Methods: HNEpC cells were cultured with four concentrations of histamine in vitro. The phosphorylation of cyclic adenosine monophosphate-responsive
element binding protein (CREB) at serine 133 and the AQP5 protein were measured by using immunocytochemistry and Western blotting. Real-time
polymerase chain reaction was used to detect AQP5 messenger ribonucleic acid (mRNA).
Results: Concentration-dependent histamine induced-inhibition of CREB phosphorylation at serine 133 in HNEpC cells was observed, and AQP5 mRNA
and protein were also downregulated in a concentration-dependent fashion.

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Conclusion: Histamine downregulates AQP5 production in HNEpC cells by inhibiting CREB phosphorylation at serine 133.
(Am J Rhinol Allergy 29, 188 –192, 2015; doi: 10.2500/ajra.2015.29.4181)

N asal airway epithelium plays an important role in maintaining logic properties of tissue and organ systems in which AQP5 is ex-

the water homeostasis of the airway.1 It secretes fluid and
determines the electrolyte composition of nasal secretions.2 A fluid
layer covers the airway surface, and it is essential to protect the
airway epithelium from inhaled xenobiotic materials.3 Hence, nasal
airway epithelium forms an important physiologic defense barrier in
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pressed.
AQP5 is closely related to water metabolism disorders in allergic
rhinitis (AR).14 It is expressed at high levels in the upper airway,
including in human nasal mucosa.15,16 AQP5 is functionally important
for regulating the airspace-capillary osmotic water permeability.17

body.
Aquaporins (AQP) are a family of small integral membrane pro-
teins that maintain airway fluid homeostasis.4,5 They can mediate
physiologic and cellular responses to changes in fluid volume and
osmolarity.6 AQPs are required for normal secretory and absorptive
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Increased protein and mucus secretion were observed in the upper
airways of mice after the deletion of AQP5 gene, possibly due to the
impaired fluid transport in the absence of AQP5 expression, as re-
ported in salivary glands.11,18 It is also one of the genes that give rise
to airway hyperactivity in AR. The airway of the AQP5 knock-out

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functions of many tissues, including lung, salivary gland, and nasal
mucosa tissues, and they provide essential systemic regulation of
water balance.7,8 One member of the AQPs family, AQP5, has been
shown in recent animal studies to be expressed in acinar epithelial
mice was hyperresponsive to cholinergic stimulation compared with
that of wild-type mice.16 AQP5 was downregulated in a rat allergic
model by inhibiting CREB phosphorylation,14 and a reduction in
human AQP5 expression has been shown to be correlated with an

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cells and airway epithelial cells.9,10 Deficiencies in the proper expres-
sion or localization of AQP5 have also been associated with defects in
water handling. Pilocarpine treatment induced a submucosal gland
fluid secretion rate in AQP5 null mice 57% lower than in wild-type
mice.11 Mutations in AQP5 that result in incorrect subcellular local-
ization of the channel in the apical plasma membrane have been
detected in individuals with Sjogren syndrome, a disorder character-
increase in MUC5AC production,19,20 which results in mucous hyper-
secretion in the nasal cavity.
AR results from type I hypersensitivity reactions associated with
immunoglobulin E, which mediates the release of histamine from
mast cells. Histamine is not the cause of allergy but an important
chemical mediator.21 It can promote allergy and inflammation,22 and

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ized by decreased salivary and lachrymal secretions.12,13 Thus, AQP5
is thought to be a key participant in the fluid secretion and a rate-
limiting factor in secretion of the submucosal serous gland, and it
plays a critical role in maintaining physiologic function of the air-
plays an important role in the secretion of submucosal glands in the
nose.23 However, little is known about the direct involvement of
histamine in airway epithelial AQP5 regulation. We propose the
hypothesis that histamine downregulates AQP5 expression via inhib-
iting CREB phosphorylation. In this study, human nasal epithelial

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way.11
It has been reported that AQP5 expression is upregulated through
phosphorylation of cyclic adenosine monophosphate (cAMP) respon-
sive element binding protein (CREB) at serine 133 (Ser133) in rat nasal
epithelial cells, and CREB is a powerful transcription factor for AQP5
expression.1 The identification of molecular mechanisms that regulate
the activity of AQP5 will likely yield useful insights into the physio-
From the 1Department of Anatomy, Schools of Medicine and Nursing Sciences, Hu-
zhou University, China, and 2Department of Anatomy, Medical College, China Three
Gorges University, Yichang City, Hubei Province, China
This study was supported by the grant from Scientific Research Foundation of Huzhou
University (RK30035)
The authors have no conflicts of interest to declare pertaining to this article
Address correspondence to Weiwei Wang, M.D., Department of Anatomy, Schools of
Medicine and Nursing Sciences, Huzhou University, No. 1, Xueshi Road, Huzhou
City, Zhejiang Province, China 313000
E-mail address: wwwhbqh@126.com
Published online March 16, 2015
Copyright © 2015, OceanSide Publications, Inc., U.S.A.
cells (HNEpC) were cultured in vitro and stimulated with histamine,
and we sought to determine whether histamine regulates the expres-
sion of AQP5 in HNEpC in vitro, and to detect possible mechanism by
which AQP5 is regulated in HNEpC.
MATERIALS AND METHODS
The stimulation of HNEpC in vitro and grouping
This study was approved by the Institutional Review Board of
Huzhou Teachers College. HNEpC (Jennio Biologic Technology,
Guangzhou, China) were cultured with RPMI-1640 (HyClone, Logan,
UT) that contained 15% fetal bovine serum (HyClone), 100 ␮/mL of
penicillin (Sigma, St. Louis, MO), and 100 ␮g/mL of streptomycin
(Sigma). When the cells reached 80% confluence, the cells were in-
duced by 0, 10⫺6, 10⫺5 or 10⫺4 mmol/L of histamine (Tocris Biosci-
ence, Ellisville, MO) for 24 hours. In this experiment, there were four
groups defined by the concentration of histamine: 0-, 10⫺6-, 10⫺5-, and
the 10⫺4-mmol/L group.

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Immunocytochemistry
The cells that grew on glass coverslips were fixed in 4% paraformal-
dehyde solution (pH 7.4) for 20 minutes at room temperature. Intrinsic
peroxidase activity was blocked with H2O2 for 10 minutes at room
temperature, then nonspecific antibody binding was blocked with non-
immune serum for 10 minutes. The cells were incubated overnight at 4°C
with antibody, a 1:250 dilution of goat-anti-AQP5 antibody (Santa Cruz
Biotechnology Inc, Santa Cruz, CA), a 1:300 dilution of rabbit-anti-phos-

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phorylated CREB (p-CREB) at Ser133 antibody (Abcam, Cambridge,
MA). After washing, the cells were incubated for 10 minutes at room
temperature with the corresponding biotin-conjugated secondary anti-
body followed by incubation with horseradish peroxidase (HRP)-

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streptavidin for 10 minutes, then incubated with diaminobenzidine for 3
minutes. A magnification of ⫻ 20 was used to examine 20 microscope
fields per section, and the results were photographed. Analysis of the
images was carried out with an Imagepro-Plus 12.0 (Media Cybernetics
Inc, Bethesda, MD), which had been programmed to measure the inte-

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gral optical density (OD) of the immunocytochemically positive areas,
and the mean OD was obtained.

Western Blotting

Total cell lysates were collected in radio-immunoprecipitation as-
say buffer (Beyotime Institute of Biotechnology, Jiangmen, Jiangsu
Province, China) to detect AQP5 protein. Nuclear protein was iso-
lated from HNEpC cells for the detection of p-CREB (Ser133) by using
a Nuclear-Cytosol Extraction Reagent Kit (Pierce, Rockford, IL). Pro-
C
Figure 1. Immunocytochemistry for p-CREB (Ser133) protein in HNEpC
cells. (A), (B), (C), and (D) represent 0-, 10⫺6-, 10⫺5-, or 10⫺4-mmol/L
groups, respectively (scale bars ⫽ 200 ␮m). Arrows represent the positive
localization of p-CREB protein.

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teins were transferred to polyvinylidene fluoride membranes (Milli-
pore Corporation, Billerica, MA) after 12% sodium dodecyl sulfate gel
electrophoresis (Beyotime Institute of Biotechnology). The mem- Statistical Analysis
branes were blocked with blocking buffer (Beyotime Institute of Bio-
SPSS 13.0 software (SPSS Inc, Chicago, IL) was used for statistical
technology) for 3 hours at room temperature, then were incubated
analysis. Statistical significance was evaluated by using analysis of

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overnight at 4°C with a 1:200 dilution of goat-anti-AQP5 antibody, a
variance, followed by a Dunnet test. Experiments were repeated five
1:250 dilution of rabbit-anti-p-CREB (Ser133) antibody, a 1:1000 dilu-
to six times for each histamine concentration group, and each exper-
tion of mouse–anti-␤-actin antibody (Abcam), or a 1:300 dilution of
iment was performed in triplicate. A p value ⬍0.05 was considered to
rabbit–anti-histone H2A-1 antibody (Abcam). The membranes were
indicate statistical significance. Each data point was expressed as the

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then incubated for 1 hour with the corresponding HRP conjugated
mean (SD).
secondary antibody at room temperature, and antibody binding was
detected with Beyond ECL Plus (Beyond). Histone H2A-1 was used as
loading controls, and p-CREB results were normalized to the histone RESULTS
H2A-1 loading control before comparison across histamine concen- Immunocytochemical detection of p-CREB (Ser133) in HNEpC and
tration groups. The density of the bands in the Western blot was the protein levels are shown in Fig. 1 and Table 1. The p-CREB protein
analyzed by using the digitalized scientific software program Quan-

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tity One (Silk Scientific Corporation, Orem, UT).
Real-Time Polymerase Chain Reaction
Total RNA from HNEpC cells was isolated by TRIzol Reagent
located in the cell nuclei of human mucosal epithelial cells was
determined. The mean OD of p-CREB protein was dose-dependent
with 10⫺6, 10⫺5, and 10⫺4 mmol/L of histamine, which resulted in
decreases of 7.63%, 28.24%, and 47.33%, respectively compared with
the 0-mmol/L group (p ⬍ 0.05). The p-CREB protein in the 10⫺5- and

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(Invitrogen Corporation, Carlsbad, CA). One microgram of total RNA
was reverse transcribed to complementary deoxyribonucleic acid
(cDNA) by using the ReverAid First Strand cDNA Synthesis Kit
(Fermentas Inc, Hanover, MD). Real-time polymerase chain reaction
was performed by using the Platinum SYBR Green qPCR Super
Mix-UDG kit (Invitrogen Corporation) and a real-time thermal cycler
(ABI 7500, Applied Biosystems, Foster, CA). The primers used are as
follows:
AQP5: 5⬘-CTGTCCATTGGCCTGTCTGTC-3⬘, 5⬘-GGCTCATACGT-
GCCTTTGATG-3⬘.
␤-actin: 5⬘-CCTGTACGCCAACACAGTGC-3⬘, 5⬘-ATACTCCT-
GCTTGCTGATCC-3⬘.
The amplification reaction was 50°C for 2 minutes and 95°C for 2
minutes, followed by 40 cycles of 95°C for 15 seconds and 60°C for 1
minute, and was terminated by a cooling step at 4°C. The mean cycle
threshold (CT) derived from the 0-mmol/L group was used as the
calibrator. The equation used was as follows:
Ratio (sample to calibrator) ⫽ 2(⫺‚‚CT).
Where ‚CT ⫽ CT(target gene) – CT(Reference gene), and ‚‚CT ⫽
‚CT(sample) – ‚CT(calibrator).
10⫺4 -mmol/L groups was decreased by 22.31% and 42.98%, respec-
tively (p ⬍ 0.05) compared with the 10⫺6-mmol/L group. Incubation
with 10⫺4 mmol/L of histamine led to a decrease of 26.60% compared
with the 10⫺5-mmol/L group (p ⬍ 0.05).
Western-blotting detection of p-CREB (Ser133) in HNEpC and the
protein level are shown in Fig. 2 and in Table 1. Consistent with the
immunocytochemical results, incubation with 10⫺6-, 10⫺5-, and 10⫺4-
mmol/L of histamine led to decreases of 12.30%, 21.63%, and 47.72%,
respectively compared with the 0-mmol/L group (p ⬍ 0.05). The
p-CREB protein assayed by Western blotting in the 10⫺5- and 10⫺4-
mmol/L groups was significantly decreased by 10.64% and 40.39%,
respectively (p ⬍ 0.05) compared with the 10⫺6-mmol/L group. In-
cubation with 10⫺4-mmol/L histamine led to a decrease of 33.29%
compared with the 10⫺5-mmol/L group (p ⬍ 0.05). Phosphorylation
of CREB at Ser133 increased in a concentration-dependent manner
after incubation of HNEpC with histamine for 24 hours.
Immunocytochemical results of AQP5 expression in HNEpC and
the protein levels are shown in Fig. 3 and in Table 1. The AQP5
protein is located in the cell membrane and cytoplasm of human
mucosal epithelial cells. By determining the mean OD of the AQP5,

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Table 1. The results of p-CREB and AQP5 in HNEpC by immunocytochemistry, Western blotting, and real-time PCR
Histamine 0 mmol/L 10ⴚ6 mmol/L 10ⴚ5 mmol/L 10ⴚ4 mmol/L
p-CREB
Immunocytochemistry 0.131 ⫾ 0.016 0.121 ⫾ 0.011a 0.094 ⫾ 0.015a,b 0.069 ⫾ 0.018a,b,c
Western blotting 0.943 ⫾ 0.098 0.827 ⫾ 0.043a 0.739 ⫾ 0.081a,b 0.493 ⫾ 0.071a,b,c
AQP5
Immunocytochemistry 0.154 ⫾ 0.017 0.136 ⫾ 0.012a 0.102 ⫾ 0.014a,b 0.083 ⫾ 0.009a,b,c
0.972 ⫾ 0.129 0.682 ⫾ 0.112a 0.382 ⫾ 0.107a,b 0.118 ⫾ 0.091a,b,c

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Western blotting
Real-time PCR 1 0.952 ⫾ 0.019a 0.785 ⫾ 0.020a,b 0.569 ⫾ 0.014a,b,c
The data are presented as mean (SD); “a” represents p ⬍ 0.05 vs the 0-mmol/L group, “b” represents p ⬍ 0.05 vs the 10⫺6-mmol/L group, “c” represents
p ⬍ 0.05 vs the 10⫺-5-mmol/L group. PCR ⫽ Polymerase chain reaction.

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Figure 2. Western blotting for p-CREB (Ser133) protein level in HNEpC
cells. Histone H2A-1 was used as loading control. Samples were analyzed by
immunoblotting with antibody against p-CREB (Ser133) and histone
H2A-1.
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Figure 4. Western blotting for AQP5 protein in HNEpC cells. ␤-actin was

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used as loading control. Samples were analyzed by immunoblotting with
antibody against AQP5 and ␤-actin.

was a concentration-dependent reduction of AQP5 protein expression

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with the protein in the 10⫺5- and 10⫺4-mmol/L groups decreased by
44.57% and 82.70%, respectively (p ⬍ 0.05) compared with the 10⫺6-
mmol/L group. We also found a significant difference between the
10⫺4-mmol/L histamine group and the 10⫺5-mmol/L group (p ⬍ 0.05).
The messenger ribonucleic acid (mRNA) levels of AQP5 are shown

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in Table 1. Incubation with 10⫺6, 10⫺5, and 10⫺4-mmol/L of histamine
led to a decrease that showed the same trend as the decreases in
protein expression with reductions of 4.80%, 21.50%, and 43.10%,
respectively compared with the 0-mmol/L group (p ⬍ 0.05). The

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mRNA levels in the 10⫺5- and 10⫺4-mmol/L groups were signifi-
cantly lower by 17.54% and 40.23%, respectively (p ⬍ 0.05) compared
with the 10⫺6-mmol/L group. And AQP5 mRNA expression was
27.52% lower after 10⫺4-mmol/L histamine incubation compared
with 10⫺5-mmol/L histamine incubation (p ⬍ 0.05).

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DISCUSSION
Since AQP1 was discovered, 13 mammalian AQPs have been de-
scribed that are distributed throughout the body.15 They are a group
of membrane transporter proteins related to water transport. Most of

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Figure 3. Immunocytochemistry for AQP5 protein in HNEpC cells. (A),
(B), (C), and (D) represent 0-, 10⫺6-, 10⫺5-, or 10⫺4-mmol/L groups,
respectively (scale bars ⫽ 200 ␮m). Arrows represent the positive localiza-
tion of AQP5 protein.
them are selectively distributed in the epithelial cells that are related
to fluid secretion or absorption.24,25 AQP5 is expressed mainly in the
membrane and cytoplasm of the epithelium in the glands, ducts, and
cilia of nasal mucosa,26 and information regarding the regulation of its
abundance and distribution is relatively limited, although results of
current studies indicate that its expression is downregulated in AR
rats.14

we found that incubation with 10⫺6, 10⫺5, and 10⫺4 mmol/L of

histamine led to decreases of 11.69%, 33.77%, and 46.10%, respectively
compared with the 0-mmol/L group (p ⬍ 0.05). Similar to the results
for p-CREB, the AQP5 protein in the 10⫺5- and 10⫺4-mmol/L groups
was significantly decreased compared with the 10⫺6-mmol/L group,
and its expression in the 10⫺4-mmol/L histamine group was de-
creased by 18.63% compared with the 10⫺5-mmol/L group (p ⬍ 0.05).
Western-blotting detection of the AQP5 protein in HNEpC con-
firmed the results of the immunocytochemistry experiments, shown
in Fig. 4 and Table 1. Incubation with 10⫺6, 10⫺5, and 10⫺4 mmol/L of
histamine led to decreases of AQP5 of 29.84%, 61.11%, and 87.86%,
respectively compared with the 0-mmol/L group (p ⬍ 0.05). There
Histamine can inhibit CREB phosphorylation at
Ser133
Histamine plays a major role in AR and causes the hypersecretion
of nasal mucosa.27 CREB is an important mediator of the effect of
histamine.28 A study showed that CREB plays an important role in
regulating histamine action at the gene expression level, and its
phosphorylation on histamine stimulation was reported.29 In the pres-
ent study, HNEpC cells were treated with four concentrations of
histamine in vitro for 24 hours. Histamine downregulated CREB phos-
phorylation at Ser133 in a concentration-dependent fashion, which
indicated a role for histamine-mediated CREB function. Hegyi et al.28
used a histidine-decarboxylase gene-targeted mouse model that

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lacked endogenous histamine to study how histamine deficiency
impacts CREB signaling, and found that cells show higher constitu-
tive CREB activity in the absence of histamine and greatly increased
intracellular cyclic adenosine monophosphate (cAMP) levels. These
data are consistent with our results. Histamine and its four receptors
represent a complex system of immune regulation with distinct ef-
fects dependent on receptor subtypes and their differential expres-
sion.30 It was reported that the histamine 3 receptor can inhibit CREB
phosphorylation,31 and histamine inhibited CREB phosphorylation at
Ser133 in this study.
Histamine downregulates AQP5 production by
inhibiting CREB phosphorylation
CREB is a well-known transcription factor that regulates the ex-
pression of genes involved in several physiologic functions.32 After
CREB is phosphorylated at Ser133, it binds as a homodimer or het-
erodimer to the conserved cAMP-response elements (CRE) of many
cAMP-responsive genes.33–35 CREB phosphorylation matches well
with the stimulation of transcription of CRE-containing genes.1
It has been reported that nuclear factor-␬B pathway also down-
regulates the expression of AQP5 in AR by inhibiting CREB phos-
phorylation at Ser133.14 Dong et al.20 and Krane et al.36 confirmed that
the mRNA level of AQP5 was significantly reduced in allergic
asthma. In this study, human nasal epithelial cells were treated with
four concentrations of histamine in vitro for 24 hours. The results of
immunocytochemistry, Western blotting, and real-time polymerase
chain reaction indicate that histamine downregulated the expression
of AQP5 protein and mRNA in a concentration-dependent fashion.
The changes of AQP5 expression were consistent with that of CREB
protein. CREB phosphorylation is involved in the regulation of AQP5
expression in rat nasal respiratory epithelial cells,1 and it was re-
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ported that the AQP5 expression is downregulated by inhibiting
CREB phosphorylation in AR rats.14 Results of a study showed that
the binding site for CREB is found in the 5⬘-flanking region of the
AQP5 gene.37 CREB is phosphorylated at Ser133, then binds as a
homodimer or heterodimer to CREB-responsive elements present at
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the promoter region of the AQP5 gene, and, finally, the gene tran-
scriptions of AQP5 are induced.1
Mucin hypersecretion is linked to several of the hallmark features
of airway inflammatory. MUC5AC is one of the representative mu-
cins, and it is the key factor in nasal diseases.38,39 Histamine down-
regulates the AQP5 production, which results in a clearance dysfunc-
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tion of the airway epithelial secretion during allergic inflammation.14
In addition, a reduction in AQP5 expression in allergic disease has
been shown to be correlated with an increase in MUC5AC mucin
production,19,20 and a recent study showed that histamine induces
D
mucin overexpression through the H1 receptor in airway epithelial
cells.40 These factors can result in the hypersecretion from the nasal
cavity, even though the AQP5 expression was downregulated in AR.
CONCLUSION
The current study demonstrated that histamine inhibits CREB
phosphorylation at the Ser133 site in HNEpC, which results in a
decrease of AQP5 expression. Hence, histamine downregulates the
AQP5 production by inhibiting CREB phosphorylation at Ser133, and
the decrease of AQP5 induces the increase of mucin production,
which results in the hypersecretion from the nasal cavity in AR. This
observation could provide a theoretical basis to study water metab-
olism disorders in AR. However, in this study, it is not clear how
histamine downregulates CREB activity. Our future work will further
elucidate the mechanism through which CREB activity is regulated.
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