The impact of inflammation and cytokine expression of PM2.5 in AML
- Authors:
- Published online on: June 13, 2018 https://doi.org/10.3892/ol.2018.8965
- Pages: 2732-2740
Abstract
Introduction
Air pollution, also known as smog, has become much more severe in China in recent years. Smog is the result of interactions between specific climatic conditions and human activities. The economic and social activities of high-density populations result in the emission of large amounts of fine particulate matter; one such common pollutant is known as particulate matter with diameter ≤2.5 µm (PM2.5) due to the aerodynamic diameter is ≤2.5 µm. When the discharge of PM2.5 exceeds the circulation and carrying capacity of the atmosphere, these fine particles accumulate in the air, leading to smog. Numerous studies have demonstrated that air pollution damages the respiratory system, cardiovascular system, and organs, including the heart and lungs (1–8) Additionally, PM2.5 increases the incidence of infectious diseases and decreases male fertility (9–13).
Leukemia, a malignant clonal disease originating from hematopoietic stem cells, is a major public health threat, and the sixth and eighth leading cause of cancer-associated mortality in men and women in China, respectively. Notably, leukemia is the leading cause of cancer-associated mortality in children and patients <35 years old. In recent years, several studies have demonstrated the association between PM2.5 and the risk of leukemia. Studies by Brosselin and Steffen have revealed that living near gas stations or garages may increase the risk of developing acute lymphoblastic leukemia and acute myeloid leukemia (AML) (14,15). Another study performed in Denmark indicated that there is an association between traffic-associated air pollution and the risk of developing AML (16).
Despite extensive studies, the mechanisms mediating the effects of PM2.5 on the occurrence and development of leukemia remain unclear. However, changes in the bone marrow microenvironment are considered to be involved in the progress of leukemia (17,18). A study performed in Taiyuan, China demonstrated that PM2.5 affects cell proliferation, but does not cause cell injury in exposed leukemia cells and that low doses of PM2.5 accelerates leukemia development through a reactive oxygen species-mediated pathway (19).
In the present study, the effects of various concentrations of PM2.5 on cell proliferation were investigated in three AML cell lines (U937, HL-60 and KG-1a). The expression levels of several cytokines, including interleukin-2 (IL-2), IL-10, IL-17A and tumor necrosis factor (TNF) α, after PM2.5 exposure in AML cell lines and rats were also evaluated, with the aim of elucidating the mechanisms through which PM2.5 affects the occurrence and development of leukemia.
Materials and methods
Reagents and cell lines
PM2.5 particles purchased from the National Institute of Standards and Technology (Gaithersburg, MD, USA) were diluted in sterilized PBS solution to 5 mg/ml and preserved at −20°C in aliquots. The samples were then diluted to a working concentration in RPMI-1640 (cat. no. SH30809.01; Hyclone; GE Healthcare Life Sciences, Logan, UT, USA) prior to use.
Three human AML cell lines (U937, HL-60 and KG-1a) were purchased from the National Infrastructure of Cell Line Resource (Beijing, China). U937 and HL-60 cells were cultured in RPMI-1640 supplemented with 10% fetal bovine serum (cat. no. 10099141; Gibco; Thermo Fisher Scientific, Inc., Waltham, MA, USA), whereas KG-1a cells were cultured in RPMI-1640 supplemented with 20% fetal bovine serum. All cell lines were cultured at 37°C in a 5% CO2 humidified atmosphere without antibiotics.
Treatment of U937, HL-60 and KG-1a cell lines
U937, HL-60 and KG-1a cells were treated with PM2.5 solution at concentrations of 0–20 mg/ml for 24, 48 and 72 h after reaching a steady-state of exponential growth in normal medium.
Measurement of cell proliferation
Cell proliferation rates were measured using a Cell Counting Kit-8 (Dojindo Molecular Technologies, Inc., Kumamoto, Japan) according to the manufacturer's protocol. The relative cell proliferation ratio (%) following treatment was compared with controls (cultured cells without PM2.5 treatment or blank controls with RPMI-1640 with 10% FBS), and calculated as follows: [(Acontrol-Ablank of control)-(Asample-Ablank of sample)]/(Acontrol-Ablank of control) ×100%.
Measurement of cytokine mRNA expression levels in AML cell lines
The mRNA expression levels of IL-2, IL-10, IL-17A, and TNFα were detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) in AML cells following treatment with 0.1 mg/ml PM2.5 solution for 0, 24, 48 and 72 h. The housekeeper gene actin β was used as a control. The RNA of cells was extracted using Trizol reagent (cat. no. 15596018; Invitrogen; Thermo Fisher Scientific, Inc.). cDNA templates from AML cell lines were prepared using a TIANScript RT kit (Tiangen Biotech, Co., Ltd., Beijing, China) according to the manufacture's protocol.
RT-qPCR cycling was performed in 96-well plates on a LightCycler 480 Real-Time PCR system (Roche Applied Science, Penzberg, Germany). The reaction was performed in a 20-µl total volume containing 10 µl SYBR Select Master mix (cat. no. 4472908; Thermo Fisher Scientific, Inc.), 1 µl of each primer (10 µM), and 2 µl template cDNA. The primer sequences used for PCR are presented in Table I. The amplification protocol consisted of an initial denaturation step at 95°C for 5 min, followed by two-step PCR for 40 cycles at 95°C for 30 sec and 60°C for 30 sec. The mRNA expression levels of each target were determined based on the cycle threshold (Cq) value for the reference and each target and calculated as 2−ΔCq (20). Three independent experiments were performed.
Measurement of protein expression levels in rats
All 26 Sprague Dawley (SD) rats were 6-week-old males (173–190 g), purchased from Charles River Laboratories (Beijing, China), and housed at a temperature of 25°C, 1.013×105 pa atmosphere, 12/12 h dark/light cycle and ad libitum access to food and water. The present study was approved by Ethics Committee of Beijing Luhe Hospital Affiliated to Capital Medical University (Beijing, China). Exposed chambers and clean chambers were constructed to raise rats. Air in the exposed chambers was the same as the true air outside, whereas air in the clean chambers was filtered to remove PM2.5 particles. Fourteen rats were kept in exposed chambers (n=8) or clean chambers (n=6) for 6 weeks (between August 9, 2016 and September 19, 2016), and 12 rats were kept in exposed chambers (n=8) or clean chambers (n=4) for 12 weeks (between August 9, 2016 and October 10, 2016). The PM2.5 concentration in the atmosphere during the study is presented in Table II.
The peripheral blood of rats was collected from hearts after feeding for 6 or 12 weeks. Blood samples were centrifuged at 1,000 × g for 20 min at room temperature to obtain serum. Milliplex Map Rat Cytokine/Chemokine Magnetic Bead Panel-Immunology Multiplex assays (cat. no. RECYTMAG-65K; EMD Millipore, Billerica, MA, USA) were used to detect the expression of cytokines in serum according to the manufacturer's protocol.
Statistical analysis
Statistical analysis was performed using Microsoft Excel 2010 (Microsoft Corporation, Redmond, WA, USA) and Graphpad Prism 5 (GraphPad Software, Inc., La Jolla, CA, USA). All data were derived from at least three independent experiments and are presented as means ± standard deviations. The results were evaluated using two-tailed unpaired Student's t-test and one-way analysis of variance (ANOVA) with Dunnett's multiple comparison post-hoc test. P<0.05 was considered to indicate a statistically significant difference. In RT-qPCR analysis, statistical significance was assumed if the 2−Δct (target mean value-reference mean value) value was >150% or <75%.
Results
Low concentrations of PM2.5 promote proliferation, whereas high concentrations of PM2.5 inhibit proliferation in AML cells
First, the effects of PM2.5 on the proliferation of AML cell lines (U937, HL-60, and KG-1a) were evaluated. The results demonstrated that 24 h of treatment with PM2.5 did not induce or inhibit the proliferation of U937 cells at any concentration. However, after 48 or 72 h of treatment, PM2.5 first promoted and then significantly inhibited the proliferation of U937 cells as the concentration of PM2.5 increased. These effects were more evident at 72 h compared with at 48 h. A similar situation was observed in HL-60 and KG-1a cells. However, the stimulatory and inhibitory effects of PM2.5 on KG-1a cells were less evident compared with those on U937 and HL-60 cells (Fig. 1).
PM2.5 significantly alters the expression of cytokines in AML cells
Next, the expression levels of IL-2, IL-10, IL-17A and TNFα were analyzed in U937, HL-60 and KG-1a cells following treatment with PM2.5. The results revealed that the mRNA expression levels of IL-2 in U937 cells, IL-17A in HL-60 cells, and IL-2 and IL-17A in KG-1a cells were below the limit of detection (data not shown). In contrast, the expression of IL-10, IL-17A and TNFα in U937 cells; IL-10 and TNFα in HL-60 cells; and IL-10 in KG-1a cells significantly increased in a time- and concentration-dependent manner (Figs. 2 and 3). Notably, IL-2 expression in HL-60 cells and TNFα expression in KG-1a also increased after treatment with 0.1 µg/ml PM2.5 for 24 h or ≥0.01 µg/ml for 72 h; however, these effects did not persist over time (Fig. 2) and did not increase as the concentration was increased (Fig. 3).
PM2.5 significantly increases serum IL-2 and IL-6 in SD rats following treatment for 12 weeks
Four cytokines, IL-2, IL-10, IL-17A and TNFα, were detected in SD rat serum using enzyme-linked immunosorbent assays following treatment with PM2.5 for 6 or 12 weeks. The results demonstrated that exposure to PM2.5 for 6 weeks did not significantly alter serum levels of IL-2, IL-10, IL-17A and TNFα in SD rats (Table III). However, when the exposure time was increased to 12 weeks, serum IL-2 and IL-10 levels in rats were significantly higher compared with those of untreated rats (Table IV).
 | Table III.Content of rat serum cell factors after raising in exposed and clean chambers for 6 weeks. |
| Table IV.Content of rat serum cell factors following raising in exposed and clean chambers for 12 weeks. |
Discussion
Several epidemiological studies have demonstrated positive associations between PM2.5 exposure and increased leukemia risk (14–16,21–23). However, the mechanism explaining this association has not yet been elucidated. The present study aimed to explain the effects of PM2.5 on the occurrence and development of leukemia through its influence on cytokines in vitro and in vivo.
In the current study, low doses of PM2.5 promoted the proliferation of AML cells (U937, HL-60, and KG-1a), whereas high doses of PM2.5 resulted in cytotoxicity, thereby inhibiting cell proliferation. Furthermore, PM2.5 exposure resulted in significantly increased levels of IL-2, IL-10, IL-17A and TNFα in AML cells. Thus, these results suggested that PM2.5 was capable of inducing an inflammatory response in human AML cells.
CD4+ T cells, also known as helper T cells, are divided into three classes: Th1, Th2, and Th17, according to their different cytokine secretion patterns. The differentiation of Th1 and Th2 cells is influenced by local environmental cytokines, and these two groups complement or antagonize each other to regulate immune functions.
IL-2 is a Th1 cytokine that is indispensable in immune system regulation. IL-2 is secreted by activated T or natural killer (NK) cells by autocrine or paracrine secretion, and serves an important role in the activation and maintenance of the immune response and in the promotion of lymphocyte development. Numerous studies have confirmed that IL-2 induces NK cells and enhances their antitumor activity (24,25). The application of IL-2 as an antitumor drug in the clinical treatment of patients with AML began in the 1980s (26). In the present study, it was revealed that IL-2 levels increased in a time- and concentration-dependent manner in HL-60 cells treated with PM2.5, but was not detected in U937 or KG-1a cells. In rats, IL-2 expression was significantly enhanced after 12 weeks of exposure to PM2.5. These results suggested that PM2.5 may affect different subtypes of AML cells in different ways; thus, there may be multiple complex cytokine networks in vivo.
IL-10 is a Th2 cytokine that has multiple pleiotropic effects on immunoregulation and inflammation, and is capable of inhibiting the synthesis of pro-inflammatory cytokines, including interferon-γ, IL-2, IL-3, TNFα and granulocyte-macrophage colony-stimulating factor, produced by macrophages and Th1 T cells (27–29). Despite the inhibitory effects of IL-10 on Th1 cytokines, certain Th1 cells are also able to produce IL-10, and a negative feedback pathway is formed when IL-10 regulates Th1 cell activation (27). Previous studies have demonstrated that IL-10 directly inhibits the proliferation and migration of effector T cells, and blocks the production of associated cytokines, serving an important role in inducing tumor immune escape. When the IL-10 content is increased, the killing effect of T cells on tumor cells is markedly inhibited (30–32). Blocking IL-10 expression in animal models improves the killing ability of the immune system on tumor cells (33,34). In addition, IL-10 has been shown to inhibit T cells, forming an immunosuppressive environment and inducing tumor immune escape by inhibiting antigen-presenting cells activation (35). In the present study, the mRNA expression levels of IL-10 were significantly increased in a time- and concentration-dependent manner following treatment of AML cell lines with PM2.5 solution. Similar results were also obtained in an in vivo experiment; that is, serum IL-10 contents were significantly increased in rats exposed to PM2.5 compared with those of unexposed rats after 12 weeks. These results demonstrate the potentially carcinogenetic effects of PM2.5 in AML.
IL-17A is a pro-inflammatory cytokine produced by activated Th17 cells, which function to amplify inflammation, and activate neutrophils to engulf and digest extracellular bacteria and molds by releasing pro-inflammatory cytokines (36). IL-17 and Th17 cells mediate carcinogenesis in rat tumor models and patients with cancer. The mechanisms through which IL-17 and Th17 cells mediate carcinogenesis involve angiogenesis and the induction of cytokines in the tumor microenvironment, which promotes tumor growth (37–40). Several studies have demonstrated that IL-17 induces IL-6 production, and IL-6 activates the signal transducer and activator of transcription 3 pathway, which then upregulates the expression of prosurvival and angiogenic genes to modulate tumor angiogenesis (41–45). The tumor promoting effects of IL-17 and Th1 exist in various types of common tumors (40,46–48). Wu et al (49) demonstrated that Th17 cells were significantly increased in the peripheral blood of patients with AML compared with that in normal healthy individuals. In addition, IL-17 content increased as the number of Th17 cells increased, resulting in promotion of bone marrow cell proliferation and inhibition of immune function. Additionally, the slow growth of TNFα in the tumor microenvironment enhanced the recruitment of IL-17-dependent bone marrow cells and promoted tumor development. In the present study, the mRNA expression of IL-17A was significantly increased in U937 AML cells a time- and concentration-dependent manner following treatment with PM2.5 solution; however, the IL-17A content in HL-60 and KG-1a cells was below the detection range. Thus, these findings indicated that different mechanisms mediated the effects of PM2.5 on AML cells. The in vivo experiment revealed no significant increases in exposed rats compared with unexposed rats after 6 or 12 weeks, indicating that the mechanisms through which PM2.5 affected AML differed in vitro and in vivo. However, further studies with increased numbers of animals are required to confirm these findings.
TNFα, which is also a Th1 cytokine, is produced ectopically by malignant and immune cells in the tumor-associated microenvironment, creating a tumor-supportive inflammatory niche that modulates the development and progression of malignant disease (50). TNFα is produced by various types of leukemia cells (51–55). In several clinical studies, a positive association between the expression levels of TNFα and adverse clinical parameters in leukemia was observed (53–57) In AML, high levels of TNFα expression are associated with greater fatigue and poorer quality of life (58). Previous studies have revealed that TNFα activates nuclear factor κB and c-Jun N-terminal kinase/activator protein-1 to exert anti-apoptotic and proproliferative effects in leukemia cells, thereby facilitating leukemia cell survival and progression (32–34, 59–61). In the current study, TNFα levels were significantly increased in U937 and HL-60 cells in a time- and concentration-dependent manner following PM2.5 treatment. In KG-1a cells, TNFα levels were also increased, although the time- and concentration-dependent effects were not as evident. This in vitro experiment reflects the potential ability of PM2.5 to promote the occurrence and development of leukemia by regulating intracellular TNFα. In vivo, significant changes in TNFα expression were not observed after 6 or 12 weeks of treatment with PM2.5, further supporting that there may be different mechanisms mediating the effects of PM2.5 on AML in vitro and in vivo. However, again, further studies with greater numbers of animals are required.
Acknowledgements
The authors would like to thank Dr Xiaokun Geng and Mr Longfei Guan (China-America Institute of Neuroscience, Beijing Luhe Hospital, Capital Medical University, Beijing, China) for their valuable technical assistance with the animal experiments.
Funding
The present study was supported by the Air Pollution Subject of Science Committee of Tongzhou District (grant no. CK2016KJ035).
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
TC performed the cell and animal experiments of the present study and analyzed the obtained data. JZ and HuZ interpreted the data. YuZ, YoZ and XZ helped TC to perform the animal experiments. DZ and YF helped with the animal experiments and participated in writing the manuscript. HeZ was a major contributor to the idea of the study and participated in writing the manuscript.
Ethics approval and consent to participate
The present study was approved by Ethics Committee of Beijing Luhe Hospital Affiliated to Capital Medical University (Beijing, China).
Consent for publication
Not applicable.
Competing interests
The authors declare they have no competing interests.
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