Overexpression of GLP-1 receptors suppresses proliferation and cytokine release by airway smooth muscle cells of patients with chronic obstructive pulmonary disease via activation of ABCA1

  • Authors:
    • Yan‑Hong Sun
    • Lan He
    • Ming‑Yu Yan
    • Rui‑Qian Zhao
    • Bin Li
    • Feng Wang
    • Ying Yang
    • Hua‑Peng Yu
  • View Affiliations

  • Published online on: May 25, 2017     https://doi.org/10.3892/mmr.2017.6618
  • Pages: 929-936
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Abstract

Glucagon-like peptide-1 (GLP‑1) is an important insulin secretagogue that possesses anti‑inflammatory effects. GLP‑1 receptor (GLP‑1R) agonists have been demonstrated to serve a pivotal role in the treatment of obstructive lung diseases, including chronic obstructive pulmonary disease (COPD). However, the specific function and underlying mechanisms of GLP‑1R in COPD remain uncertain. The aim of the present study was to investigate the action and underlying mechanisms of GLP‑1R in airway smooth muscle (ASM) cells from COPD patients. GLP‑1R expression levels were markedly decreased in ASM cells from COPD patients compared with those from healthy controls. ASM cell proliferation and migration, and the levels of the inflammatory cytokines interleukin (IL)‑1β, IL‑4, tumor necrosis factor (TNF)‑α, and granulocyte‑macrophage colony‑stimulating factor (GM‑CSF) were measured. Transfection of pcDNA3.1‑GLP‑1R had inhibitory effects on ASM cell proliferation and migration, whereas GLP‑1R small interfering (si)RNA reversed these effects. Furthermore, the present study demonstrated that GLP‑1R overexpression markedly suppressed IL‑1β, IL‑4, TNF‑α and GM‑CSF levels. GLP‑1R overexpression upregulated the expression levels of adenosine triphosphate‑binding cassette, subfamily A, member 1 (ABCA1) in ASM cells, and the effects of GLP‑1R on cell proliferation and migration, and inflammatory cytokine expression in ASM cells was abolished by siRNA‑mediated silencing of ABCA1. The results of the present study suggested that GLP‑1R contributes to COPD pathology, potentially via an ABCA1‑mediated pathway.

Introduction

Chronic obstructive pulmonary disease (COPD), a chronic inflammatory disease involving the airways and lung parenchyma (1), is currently a primary cause of disability and death worldwide (2,3). COPD is characterized by various clinical conditions, including emphysema and chronic bronchitis (4). It has been reported that airway inflammation serves a significant role in COPD, although the precise role remains unclear (5). The inflammatory process has been demonstrated to be involved in the complex pathogenesis of COPD (6), and the inflammatory response in COPD is associated with increased airway smooth muscle (ASM) cell hyperplasia, which results in increased ASM mass and small airway remodeling (7). As a result of airway wall remodeling in patients with COPD, ASM cells may produce inflammatory mediators (8). Thus, ASM cells may be a novel therapeutic target for the treatment of inflammation and airway remodeling in COPD patients.

Mortality rates and lung function have previously been improved by glucagon-like peptide 1 (GLP-1) in a model of experimental obstructive lung disease in female mice (9). GLP-1, a potent glucoincretin hormone, is secreted by intestinal L-cells (10). GLP-1 increases insulin secretion and production via its receptor (GLP-1R) in pancreatic β-cells (11). GLP-1 additionally exerts various effects outside the pancreas, including regulation of food intake and appetite (12), inhibition of gastrointestinal motility and secretion (13) and a cardioprotective effect (14,15). GLP-1 acts via GLP-1R on various types of target cells (11,16); GLP-1R is expressed in the pancreatic islets, heart, brain, kidney, gastrointestinal tract and lungs (15,17,18). GLP-1 serves a role in inflammation and may inhibit lipopolysaccharide (LPS)-induced cytokine secretion in various types of cells, including peritoneal macrophages and cortical astrocytes (1921). However, although GLP-1R serves a role in obstructive lung disease, its exact underlying mechanisms remain unclear.

Hu et al (22) demonstrated that G protein-coupled receptor 119 (GPR119) significantly increased the expression levels of adenosine triphosphate-binding cassette, subfamily A, member 1 (ABCA1) via GLP-1R, and ABCA1 expression levels were markedly reduced by small interfering (si)RNA-mediated silencing of GLP-1R in a THP-1 macrophage cell line. ABCA1 is a member of a highly conserved transmembrane transport protein family, and is expressed in various mammalian tissues and cells (23,24). ABCA1 serves a crucial role in pulmonary diseases and abnormalities (25), and ABCA1 overexpression in mouse vascular endothelial cells has been associated with ovalbumin-induced neutrophilic airway inflammation (26,27). Therefore, the present study hypothesized that GLP-1R may serve an important role in COPD, and that ABCA1 is involved in the effects of GLP-1R. ASM cells were isolated from patients with COPD and a GLP-1R-overexpressing cell model was established to investigate the function and underlying mechanisms of GLP-1R. The present study provided evidence that GLP-1R is associated with ASM cell proliferation and the secretion of inflammatory cytokines.

Materials and methods

Subjects

The present study was approved by the Ethics Committee of the Zhujiang Hospital, Southern Medical University (Guangzhou, China). Written informed consent was obtained from each subject. Healthy controls (n=8) and patients with COPD (n=12) were recruited (Table I) from the Department of Respiratory Diseases of Zhujiang Hospital.

Table I.

Characteristics of subjects.

Table I.

Characteristics of subjects.

CharacteristicHealthy subjects (n=8)COPD patients (n=12)
Age (years)44.6±4.15 65.41±2.748a
Gender (male:female)5:34:6
Duration of COPD (years)NA16.35±2.28
FEV1 (% predicted)103.9±4.08 58.49±6.91a
FVC (% predicted)109.7±6.198.54±4.35
FEV1/FVC ratio (%)86.39±3.24 50.37±7.11a

{ label (or @symbol) needed for fn[@id='tfn1-mmr-16-01-0929'] } Data are expressed as the mean ± standard error.

a P<0.05 compared with healthy subjects. FVC, forced vital capacity; NA, not applicable; COPD, chronic obstructive pulmonary disorder; FEV1, forced expiratory volume at timed intervals of 1.0 sec; NA, not applicable.

ASM cell culture and transfection

ASM cells were isolated from bronchial biopsy specimens according to a method described previously (28). Isolated human ASM cells from eight healthy donors and twelve COPD donors were used at passage 3–4. Cells were maintained in Dulbecco's modified Eagle's medium (Invitrogen; Thermo Fisher Scientific, Inc., Waltham, MA, USA) supplemented with 20 µg/ml streptomycin, 4 mM L-glutamine, 2.5 µg/ml amphotericin B, 20 U/l penicillin and 10% fetal bovine serum (FBS; Invitrogen; Thermo Fisher Scientific, Inc.). Human GLP-1R cDNA was purchased from OriGene Technologies, Inc. (Rockville, MD, USA) and GLP-1R cDNA was inserted into the HindIII/EcoRI site of pcDNA3.1 (Invitrogen; Thermo Fisher Scientific, Inc.) to form pcDNA3.1-GLP-1R. Cells were transfected with pcDNA3.1-GLP-1R or pcDNA3.1 vectors using Lipofectamine 2000™ (Invitrogen; Thermo Fisher Scientific, Inc.) according to the manufacturer's protocol.

MTT assay

ASM cell proliferation was determined by MTT assay as described previously (29). A total of 72 h following transfection, 5 mg/ml MTT was added to cells, which were subsequently incubated for 4 h. Dimethyl sulfoxide (150 µl) was added to dissolve the insoluble purple formazan. The colorimetric method is based on the reduction of the soluble tetrazolium dye MTT to its insoluble formazan. Absorbance was measured at a wavelength of 490 nm using a microplate reader.

Cell migration assay

ASM cell migration was measured using Transwell cell culture chambers (8.0-µm pore size; EMD Millipore, Billerica, MA, USA) as described previously (30). ASM cells were transfected with pcDNA301-GLP-1R or GLP-1R siRNA. Cells were trypsinized and seeded into the upper chamber of the Transwell insert (1×105 cells/well) and medium containing 10% FBS was added to the lower chamber. After 24 h of incubation, Giemsa dye was used to stain migrated cells for observation. Migrated cells were quantified under a light microscope (magnification, ×200) (31).

Enzyme-linked immunosorbent assays (ELISA)

The culture supernatants of ASM cells were collected and centrifugation was performed for 10 min at 1,500 × g and 4°C to remove particles and polymers. Interleukin (IL)-6 and -8, tumor necrosis factor (TNF)-α, and granulocyte-macrophage colony-stimulating factor (GM-CSF) cytokine levels in ASM cell culture supernatants were measured using commercial ELISA kits (catalog nos. D6050, D8000C, DTA00C and DGM00, respectively; R&D Systems, Inc., Minneapolis, MN, USA) according to the manufacturer's protocol.

Reverse transcription-quantitative polymerase chain reaction (RT-qPCR)

Total cellular RNA was extracted from ASM cells using TRIzol® reagent (Invitrogen; Thermo Fisher Scientific, Inc.). Total RNA (5 µg) was used to reverse transcribe first-strand cDNA using a High-Capacity cDNA Archive kit (Applied Biosystems; Thermo Fisher Scientific, Inc.). GLP-1R and ABCA1 transcripts were quantified using SsoFast EvaGreen® Supermix (Bio-Rad Laboratories, Inc., Hercules, CA, USA) according to the manufacturer's protocol and the amplification was performed using a ABI PRISM 7900HT sequence detection system (Applied Biosciences; Thermo Fisher Scientific, Inc.). The following PCR conditions were performed in this assay: 95°C for 10 min; followed by 40 cycles of 95°C for 30 sec, 55°C for 10 sec and 72°C for 45 sec, followed by a final elongation step at 72°C for 5 min. The following primers were used: GLP-1R, 5′-TCAAGGTCAACGGCTTATTAGTGAA-3′ (forward) and 5′-CCCAAGTGATGCAAGCAGAG-3′ (reverse); ABCA1, 5′-AACAGTTTGTGGCCCTTTTG-3′ (forward) and 5′-AGTTCCAGGCTGGGGTACTT-3′ (reverse); β-actin, 5′-TCATGAAGTGTGACGTTGACATCCGT-3′ (forward) and 5′-CTTAGAAGCATTTGCGGTGCACGATG-3′ (reverse). Results were calculated using the 2−ΔΔCq method, and are expressed as fold change compared with control values following normalization against β-actin (32).

Western blotting

Protein expression levels of GLP-1R and ABCA1 were measured by western blotting. Proteins were isolated from ASM cells using radioimmunoprecipitation assay lysis buffer (Invitrogen; Thermo Fisher Scientific, Inc.), subsequently, protein (40 µg per lane) was separated by 10% SDS-PAGE and subsequently transferred to a polyvinylidene difluoride membrane. Membranes were incubated with rabbit polyclonal anti-GLP-1R (1:1,000; 1 µg/ml; catalog no. ab39072), mouse monoclonal anti-ABCA1 (1:500; catalog no. ab18180) or mouse monoclonal anti-β-actin (1:5,000; 1 mg/ml; catalog no. ab8226) antibodies (Abcam, Cambridge, MA, USA) overnight at 4°C. Subsequently, the membrane was probed with horseradish peroxidase-conjugated goat anti-rabbit IgG (1:3,000; catalog no. ab6721; Abcam Cambridge, MA, USA) or rabbit anti-mouse IgG (1:2,000; catalog no. ab6728; Abcam.) for 1 h at room temperature. Protein bands were developed with an Enhanced Chemiluminescence detection kit (GE Healthcare Life Sciences, Chalfont, UK), and visualized and quantified using Image-Pro Plus 6.0 software (Media Cybernetics, Inc., Rockville, MD, USA).

RNA silencing

GLP-1R- and ABCA1-silenced cells were generated using Lipofectamine 2000 reagent according to the manufacturer's protocol. For cells transfected with pcDNA3.1-GLP-1R vector + ABCA1 or mock siRNA, co-transfection was performed. GLP-1R and control siRNAs were synthesized by Shanghai GenePharma Co., Ltd. (Shanghai, China). The sequences of the siRNA oligomers for GLP-1R were as follows: Forward, 5′-UCAUCAAGCUGUUUACAGATT-3′ and reverse, 5′-UCUGUAAACAGCUUGAUGAAG-3′. The scrambled siRNA sequences of GLP-1R were as follows: Forward, 5′-UGUGGAUGACUGAGUACCUGA-3′ and reverse, 5′-UCAGGUACUCAGUCAUCCACA-3′. ABCA1 siRNA was purchased from Santa Cruz Biotechnology, Inc. (Dallas, TX, USA; catalog no. sc-41136). The sequences of the siRNA oligomers for ABCA1 were as follows: Forward, 5′-GAACCUCACUUAGAAGAUU-3′ and reverse, 5′-UUCUUGGAGUGAAAGUCUUCU-3′. The scrambled siRNA sequences used for ABCA1 were the same as scrambled GLP-1R siRNA sequences.

Statistical analysis

All statistical analyses were performed using SPSS software version 13.0 (SPSS, Chicago, IL, USA). Data are expressed as the mean ± standard error. Differences between two groups were determined by the unpaired Student's t-test, and differences between multiple groups were determined by one-way analysis of variance followed by Fisher's least significant difference test. P<0.05 was considered to indicate a statistically significant difference. All experiments were performed in quadruplicate and repeated three times.

Results

GLP-1R mRNA and protein expression levels are reduced in ASM cells from COPD patients

The present study examined GLP-1R mRNA expression levels in ASM cells obtained from patients with COPD and healthy controls (Table I) by RT-qPCR. GLP-1R mRNA expression levels were significantly decreased in ASM cells from patients with COPD, compared with healthy control cells (P<0.05; Fig. 1A). GLP-1R protein expression levels demonstrated the same effect, as revealed by western blot analysis (P<0.05; Fig. 1B). To further investigate the effects of GLP-1R in ASM cells from COPD patients, overexpression or silencing of GLP-1R in ASM cells was performed. As revealed by RT-qPCR (Fig. 1C) and western blot analysis (Fig. 1D), the mRNA and protein expression levels of GLP-1R were significantly increased in ASM cells transfected with pcDNA3.1-Glp-1R for 72 h, and significantly decreased in those transfected with GLP-1R siRNA for 48 h. The mRNA and protein expression levels of GLP-1R were additionally measured in ASM cells transfected with pcDNA3.1-GLP-1R or GLP-1R siRNA for 24, 48, 72 or 96 h. The results indicated that the mRNA and protein expression levels of GLP-1R were significantly increased in ASM cells transfected with pcDNA3.1-Glp-1R, and significantly decreased in those transfected with GLP-1R siRNA (data not shown).

Effect of GLP-1R overexpression on ASM cell proliferation and migration

ASM cells from COPD patients demonstrated reduced proliferation following GLP-1R overexpression compared with the pcDNA3.1 empty-plasmid group Additionally, ASM cells transfected with GLP-1R siRNA exhibited increased proliferation by 32% compared with the siMock group (Fig. 2A). ASM cell migration was subsequently determined, and the results were similar to the proliferation study. GLP-1R overexpression suppressed the migration of ASM cells, whereas silencing increased ASM cell migration (Fig. 2B). These data indicated that GLP-1R overexpression reduces cell proliferation and migration, and therefore may serve a role in airway remodeling in COPD patients.

Effect of GLP-1R overexpression on IL-6, IL-8, TNF-α and GM-CSF release

To determine whether GLP-1R overexpression mediates ASM cell inflammatory cytokine release, the levels of IL-6, IL-8, TNF-α and GM-CSF were measured. Cultured ASM cells isolated from patients with COPD released increased levels of IL-6, IL-8, TNF-α and GM-CSF compared with ASM cells from healthy control subjects (P<0.05; Fig. 3A). In addition, GLP-1R overexpression inhibited the release of IL-6, IL-8, TNF-α and GM-CSF, whereas its ablation increased the release of these inflammatory cytokines (Fig. 3B-E).

GLP-1R overexpression markedly upregulates ABCA1 expression levels

GLP-1R may upregulate the expression levels of ABCA1, and previous studies have indicated that ABCA1 serves an important role in airway inflammation (23,27). Thus, the present study aimed to determine the effects of GLP-1R on ABCA1 expression levels. RT -qPCR and western blotting were performed to assess the expression levels of ABCA1 in ASM cells obtained from patients with COPD and healthy control subjects. mRNA (Fig. 4A) and protein (Fig. 4B) expression levels of ABCA1 were reduced in ASM cells from COPD patients compared with the healthy control subjects (P<0.05). Furthermore, GLP-1R overexpression increased the expression levels of ABCA1 in ASM cells obtained from patients with COPD, whereas GLP-1R siRNA decreased ABCA1 expression levels (P<0.05; Fig. 4C and D).

GLP-1R-mediated cell proliferation, migration and cytokine release is dependent on ABCA1 expression

The above results suggested that GLP-1R increases the expression levels of ABCA1, and it was therefore hypothesized that the effects of GLP-1R on ASM cell proliferation, migration and cytokine release are dependent on altered ABCA1 expression levels. To further investigate the interaction between ABCA1 and GLP-1R in ASM cells obtained from patients with COPD, ABCA1-silenced ASM cells were established. As presented in Fig. 5A, ABCA1 siRNA markedly inhibited the mRNA expression levels of ABCA1. Treatment with pcDNA3.1-GLP-1R significantly inhibited proliferation (Fig. 5B) and migration (Fig. 5C) of ASM cells from COPD patients, whereas this effect was ameliorated by co-transfection with ABCA1 siRNA (P<0.05). IL-6, IL-8, TNF-α and GM-CSF levels were additionally measured, and the results indicated that ABCA1 siRNA reversed the GLP-1R overexpression-induced decrease in IL-6, IL-8, TNF-α and GM-CSF expression levels (P<0.05; Fig. 5D).

Discussion

The present study demonstrated decreased expression levels of GLP-1R and ABCA1 in ASM cells from patients with COPD. Furthermore, overexpression of GLP-1R suppressed proliferation and cytokine release by ASM cells from patients with COPD via increased ABCA1 expression levels.

GLP-1 serves a cardioprotective role in humans following myocardial infarction (MI) and in animal models of MI (14). Liu et al (33) demonstrated that chronic treatment with GLP-1 or AC3174 improves glucose metabolism, fluid balance and respiratory efficiency in a rat model of congestive heart failure, compared with vehicle control animals. GLP-1Rs are known to serve an important role in models of experimental obstructive lung disease in female mice (9); GLP-1R agonists were demonstrated to reduce mortality rates and improve lung function, and may have therapeutic potential for the treatment of obstructive pulmonary diseases (9). However, the specific function and underlying mechanisms of action remain unclear. Consistent with this study, the present study revealed that GLP-1R serves a crucial role in COPD in vitro. GLP-1R overexpression significantly suppressed proliferation and cytokine release by ASM cells from patients with COPD, which may serve roles in airway remodeling and inflammation.

Notably, COPD is analogous to asthma in that the two diseases are associated with chronic inflammation and smooth muscle hyperplasia. ASM cells may mediate immune modulation and inflammation in the airway via secretion of inflammatory mediators and cytokines (34). Furthermore, ASM cell hyperplasia contributes to an increase in ASM mass and results in small airway remodeling in COPD (7). Adenosine triphosphate-binding cassette transporters, including ABCA1, are known to be important in the pathogenesis of ASM cells. ABCA1 may serve a critical role in airway diseases, including asthma, via dysregulation of cholesterol homeostasis (35). Although the function of ABCA1 has been well characterized in ASM cells, its role in COPD remains unclear.

The ABCA1 gene has previously been demonstrated to be a target of liver X receptors (LXRs) (7,26,33); macrophage expression of ABCA1 and intestinal cholesterol absorption was abolished in LXR-null mice. Mostafa et al (36) revealed that GLP-1 may modulate ABCA1 expression levels in adipocytes via an LXR-α-mediated process. Hu et al (22) demonstrated that GLP-1R-silencing markedly inhibits ABCA1 expression in THP-1 macrophages. Consistent with these studies, the present study revealed that GLP-1R overexpression promoted ABCA1 expression levels, whereas GLP-1R silencing inhibited its expression levels. Using siRNA knockdown approaches, ABCA1 was demonstrated to be necessary for GLP-1R-induced cell proliferation, migration and cytokine release inhibition in ASM cells.

In conclusion, the present study revealed that overexpression of GLP-1R significantly reduces proliferation, migration and cytokine release in ASM cells from COPD patients; this involved a significant increase in ABCA1 expression levels. This provided evidence to suggest that GLP-1R may be a potential therapeutic target for the treatment of COPD.

Glossary

Abbreviations

Abbreviations:

GLP-1

glucagon-like peptide-1

COPD

chronic obstructive pulmonary disease

ASM

airway smooth muscle

ABCA1

adenosine triphosphate-binding cassette, subfamily A, member 1

LPS

lipopolysaccharide

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Volume 16 Issue 1

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Sun YH, He L, Yan MY, Zhao RQ, Li B, Wang F, Yang Y and Yu HP: Overexpression of GLP-1 receptors suppresses proliferation and cytokine release by airway smooth muscle cells of patients with chronic obstructive pulmonary disease via activation of ABCA1. Mol Med Rep 16: 929-936, 2017
APA
Sun, Y., He, L., Yan, M., Zhao, R., Li, B., Wang, F. ... Yu, H. (2017). Overexpression of GLP-1 receptors suppresses proliferation and cytokine release by airway smooth muscle cells of patients with chronic obstructive pulmonary disease via activation of ABCA1. Molecular Medicine Reports, 16, 929-936. https://doi.org/10.3892/mmr.2017.6618
MLA
Sun, Y., He, L., Yan, M., Zhao, R., Li, B., Wang, F., Yang, Y., Yu, H."Overexpression of GLP-1 receptors suppresses proliferation and cytokine release by airway smooth muscle cells of patients with chronic obstructive pulmonary disease via activation of ABCA1". Molecular Medicine Reports 16.1 (2017): 929-936.
Chicago
Sun, Y., He, L., Yan, M., Zhao, R., Li, B., Wang, F., Yang, Y., Yu, H."Overexpression of GLP-1 receptors suppresses proliferation and cytokine release by airway smooth muscle cells of patients with chronic obstructive pulmonary disease via activation of ABCA1". Molecular Medicine Reports 16, no. 1 (2017): 929-936. https://doi.org/10.3892/mmr.2017.6618