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Molecular and Cellular Microbiology (MCM)  |  Host-Microbe Interaction and Pathogenesis

Microbiol. Biotechnol. Lett. 2022; 50(2): 293-300

https://doi.org/10.48022/mbl.2112.12003

Received: December 16, 2021; Revised: March 4, 2022; Accepted: March 4, 2022

Lipoteichoic Acid Isolated from Staphylococcus aureus Induced THP-1 Cell Apoptosis through an Autocrine Mechanism of Cytokines and SOCS-1-Mediated Bcl2 Inhibition

Boram Jeon1, Hangeun Kim2*, and Dae Kyun Chung1,2,3*

1Graduate School of Biotechnology, Kyung Hee University, Yongin 17104, Republic of Korea
2Research and Development Center, Skin Biotechnology Center Co., Ltd., Yongin 17104, Republic of Korea
3Skin Biotechnology Center, Kyung Hee University, Suwon 16229, Republic of Korea

Correspondence to :
H. Kim,                  dkchung@khu.ac.kr
D. K. Chung,           hkim93@khu.ac.kr

Lipoteichoic acid (LTA) regulates the immune system, including inflammatory responses, through TLR2-mediated signaling pathways. LTA isolated from Staphylococcus aureus (aLTA) has been shown to induce apoptosis, but the detailed mechanism has not been identified. We found that aLTA induced apoptosis through an autocrine mechanism in the human monocyte-like cell line, THP-1. We observed that the expression level of the anti-apoptosis protein, Bcl2, was suppressed in LTA-treated THP-1 cells. In addition, the cytokines, TNF-α and IFN-γ, which have been shown to induce apoptosis in some cell lines, were involved in THP-1 cell death via the modulation of Bcl2. The suppression of Bcl2 by aLTA was recovered when the negative regulator, SOCS-1, was knocked down. Taken together, these results showed that aLTA induced apoptosis in THP-1 cells through an autocrine mechanism of cytokines and SOCS-1-mediated Bcl2 inhibition.

Keywords: Lipoteichoic acid, S. aureus, apoptosis, Bcl2, SOCS-1, cytokines

Graphical Abstract


Apoptosis, or programmed cell death, is an important immune system function triggered by various signals [1]. Many studies have shown that cellular apoptosis is regulated by the Bcl2 protein family and caspase family [2]. Two members of the Bcl2 family play roles in apoptosis. Bcl2 protein is involved in suppression of apoptosis, while Bax promotes apoptosis. Caspases are a family of cysteine protease enzymes that play an important role in programmed cell death including apoptosis, pyroptosis, and necroptosis. Increased caspase 3 activity is considered a central executioner of the caspase family [3].

It seems that LTA can regulate apoptosis-related pathways. Highly purified LTA from S. aureus (aLTA) inhibits spontaneous apoptosis, increasing the lifespan of polymorphonuclear neutrophil granulocytes [4]. Conversely, LTA of Clostridium butyricum inhibits the inflammatory response and apoptosis induced by aLTA in HT-29 cells [5]. LTA isolated from Enterococcus faecalis induces human osteoblast-like MG63 cell apoptosis by down-regulation of Bcl2 antiapoptotic protein, upregulation of Bax proapoptotic protein, and elevation of caspase-3 activity [6].

aLTA, one of the cell wall components of S. aureus, is considered a virulence factor that affects infection and immunity to the host of S. aureus [7]. Generally, LTA is composed of phosphate chains and glycolipids and interacts with toll-like receptor (TLR) 2, CD36, and a TLR-independent system. However, the immunomodulatory ability of LTA depends on the species of Gram-positive bacteria [8, 9]. For example, aLTA significantly increases the production of inflammatory cytokines and causes lung inflammation and circulation disorders.

There are no reports that aLTA induces apoptosis in THP-1 cells. Here, we demonstrated that aLTA induces THP-1 apoptosis through autocrine function of cytokines and SOCS-1-mediated inhibition of Bcl2.

Cell culture and treatment

THP-1 cells, a human monocyte-like cell line, were purchased from Korean Cell Line Bank (KCLB 40202) and maintained in RPMI-1640 medium with 10% fetal bovine serum (FBS), 2 mM L-glutamine, 100 U/ml penicillin, and 100 μg/ml streptomycin in a humidified 37℃ incubator with 5% CO2. For the cell viability assay, cells (1 × 104 cells/well) were seeded in a 96-well plate and treated with LTA, followed by pretreatment with anti-TNFRII (Clone #22210, R&D Systems) and anti- IFNγRI (Clone #92101, R&D Systems) for the indicated dose and time. For siRNA transfection, cells (1 × 105 cells/well) were seeded in 12-well plates and transfected with negative control siRNA (QIAEN, USA), siCaspase RNA (Qiagen, Hs_CASP1_12, 14, 15, 22 for Casps1, Hs_CASP3_7 for Caspase 3, Hs_CASP7_5 for Caspase 7), or siNegative regulators (QIAGEN, Hs_TNFAIP3_4 for A20, Hs_TNIP1_6 for Abin-1, Hs_CYLD_4 for CYLD, Hs-SOCS1_1, 4, 5, 6 for SOCS-1, Hs_SOCS3_1, 4, 6, 7 for SOCS-3; Santa Cruz Biotechnology, sc-39098 for IRAK-M) after combination with Lipofectamine RNAiMAX Transfection Reagent (Thermofisher Scientific, USA). After 48 h of transfection, cells were treated with 100 μg/ml LTA for the indicated time.

LTA preparation

LTA was isolated from S. aureus (ATCC 25923; aLTA) as previously described [10]. Protein and endotoxin contamination were examined using silver staining and an endotoxin assay kit (GenScript, USA), respectively, which confirmed purified LTA.

WST-1 cell viability assay

Cells were incubated with 10 μl/well cell proliferation reagent WST-1 for 30 min. Then, absorbance of samples at 450 nm was measured by a microplate reader against a background of blank control.

Quantitative PCR

To measure the level of mRNA expression, THP-1 cells were stimulated with aLTA and total RNA was isolated using RNA-Bee reagent (CS-104B, AMSBIO, USA). For cDNA synthesis, the isolated total RNA and iScript cDNA synthesis kit (Bio-Rad, USA) were used. Caspase and Bcl2 mRNA expression were quantified using realtime PCR (CFX Connect™ Real-Time PCR Detection system, Bio-Rad). The following sequences for forward and reverse primer pairs were used: 5'-TGTGGAAGAGCAGAAAGCGA- 3' and 5'-CCCTGGTGTGGTGTGGTTTA- 3' for Caspase-1, 5'-AAAGAGGAAGCACCAGAACC-3' and 5'-GGGTCAGGAACTTCTGCGAG -3' for Caspase-3, 5'-GTGGGAACGATGGCAGATGA-3' and 5'-GAGGGA CGGTACAAACGAGG-3' for Caspase-7, 5'-CTGCACCTG ACGCCCTTCAC-3' and 5'-CACATGACCCCACCGA ACTC-3' for Bcl2, and 5'-AAGGTCGGAGTCAACGGATT- 3' and 5'-GCAGTGAGGGTCTCTCTCCT-3' for glyceraldehyde- 3-phosphate dehydrogenase (GAPDH). mRNA was normalized to GAPDH.

Western blot analysis

After stimulating THP-1 cells with aLTA for an appropriate time, protein samples were prepared using 2X reducing buffer. Proteins were separated using a 12% SDS-PAGE system (25 mM Tris, 250 mM glycine, 0.1% SDS) and transferred to a polyvinylidene fluoride (PVDF) membrane for overnight. The membrane was blocked with TBS-T buffer (20 mM Tris-HCl, 150 mM NaCl, 0.05% Tween-20, 5% skim milk) for 1 h at room temperature (RT). The primary antibodies and HRP-conjugated secondary antibodies diluted in TBS-T buffer were sequentially treated on the membrane, and the target protein was visualized using the enhanced chemiluminescence (ECL) reagents (GE Healthcare, UK) and X-ray film. Anti-Caspase-1, anti-Caspase-3, anti-Caspase- 7, anti-Cytochrome C, anti-Bcl2, anti-A20, anti-Abin1, anti-SOCS-1 (Cell Signaling Technology, USA), and anti-β-actin (Santa Cruz Biotechnology, USA) antibodies were used in this study.

Caspase-3 activity assay

Caspase-3 activity assay was performed with a Caspase-3 Assay Kit (Abcam, USA) according to the manufacturer’s instructions. Briefly, cells were resuspended in chilled Cell Lysis Buffer and incubated on ice for 10 min. Cytosolic extract was transferred to a fresh tube and subjected to the assay. Then, 50 μl of 2X reaction buffer and 5 μl of the 4 mM DEVD-p-Na substrate were added to each sample and incubated at 37℃ for 60 min. Colorimetric change was determined on a microplate reader (OD 400-405 nm).

Annexin V staining

THP-1 apoptosis was examined by flow cytometry using the Annexin V-FITC/propidium iodide apoptosis assay (Abcam) according to the manufacturer’s instructions. Briefly, washed cells were resuspended in 100 μl of Annexin V-PI staining solution and incubated in the dark at room temperature for 10 min. Cells were centrifuged at 400 ×g for 5 min, and supernatant was discarded. After adding 200 μl of PBS, cells were examined immediately by flow cytometry.

Data analysis

Statistical analysis of the experimental data was performed using two-tailed Student’s t test, and significant differences of the means between groups were assessed by one-way ANOVA, two-way ANOVA or unpaired twotailed t test. The data shown are representative results of the mean ± standard deviation (SD) of triplicate experiments. Differences were considered statistically significant when the p value was < 0.05.

aLTA induced THP-1 apoptosis

In a previous study, we found that aLTA significantly induced manganese superoxide dismutase (MnSOD) production by 28.3-fold in THP-1 cells [11]. aLTA did not affect THP-1 viability in low dosages. However, 100 μg/ ml aLTA induced THP-1 cell toxicity and significantly inhibited cell growth with 72 h of treatment (Fig. 1A). Dual staining of THP-1 using anti-annexin V antibody and propidium iodide (PI) indicates that 100 μg/ml aLTA induced cell apoptosis as well as necrosis in a timedependent manner (p = 0.0022) (Fig. 1B). Data suggest that aLTA induced THP-1 cell apoptosis at high doses.

Figure 1.LTA induced THP-1 apoptosis. (A) THP-1 cells were treated with indicated doses of LTA for indicated times. Cell viability was examined by WST-1 assay. Data are displayed as mean ± SD of three independent experiments. Statistical analysis was conducted with one-way ANOVA and Tukey’s statistical test. **p < 0.01 compared to 0 h. (B) LTA-treated cells were stained with anti-Annexin V and anti-PI antibodies, and apoptotic cells were analyzed by FACS analysis. Analysis were performed independently in triplicate and representative figure was shown. Statistical analysis was conducted with two-way ANOVA test.

aLTA induced THP-1 apoptosis by caspase 3 activation

The gene expression levels of caspases were examined by real-time PCR after aLTA treatment for indicated times. Caspase 1 gene expression was upregulated by 2.5-fold with 6 h and 24 h of aLTA treatment. The gene expression level of Caspase 3 was reduced by aLTA treatment up to 6 h and restored at 24 h. Caspase 7 gene expression was significantly increased at 6 h and diminished at 24 h after aLTA treatment (Fig. 2A).

Figure 2.Caspase 3 was involved in LTA-mediated THP-1 apoptosis. (A) THP-1 cells were treated with 100 μg/ml LTA for indicated times, and mRNA levels of caspases were examined by real-time PCR. (B) Caspase 1 was detected by western blot after LTA treatment. (C) Caspase 3 activity was examined from the cytosolic fraction of LTA-treated THP-1 cells. (D) THP-1 cells were transiently transfected with siRNAs for caspases, and transfectants were treated with 100 μg/ml LTA for 48 h. Cell viability was examined by WST-1 assay. Data are displayed as mean ± SD of three independent experiments. Statistical analysis was conducted with one-way ANOVA and Tukey’s statistical test. *p < 0.05; **p < 0.01 compared to 0 h.

Next, the active forms of caspases were examined. The preforms of Caspase 1 increased with 6 h of treatment and peaked at 72 h. Cleaved Caspase 1 was dramatically increased at 6 h and slightly decreased at 72 h, suggesting that Caspase 1-mediated pyroptosis may be involved in aLTA-mediated THP-1 cell death (Fig. 2B). Although gene expression was reduced by aLTA, Caspase 3 activity was significantly increased at 6 h and 24 h of treatment with aLTA-treated THP-1 cell extracts (Fig. 2C). To confirm the role of caspases in aLTA-mediated THP-1 apoptosis, siRNAs were transfected into THP-1 cells and transfectants were treated with aLTA to induce apoptosis. As shown in the previous results, aLTA reduced cell viability in control siRNA-transfected cells. aLTA did not alter the cell viability of transfectants using siCaspase 1 and siCaspase 7. However, the viability of siCaspase 3- transfected cells increased upon exposure to aLTA, suggesting that aLTA-mediated THP-1 apoptosis is induced by Caspase 3 activation (Fig. 2D).

THP-1 apoptosis is mediated by autocrine function of cytokines

aLTA significantly induced cytokines, including TNF- α and IFN-γ, in THP-1 cells (Data not shown). The effects of these cytokines on THP-1 apoptosis were examined. When cells were blocked with anti-TNF-α receptor, cell viability increased more significantly with aLTA at 48 h and 72 h than in only aLTA-treated cells. As shown in Fig. 1, aLTA decreased cell viability at 48 h and 72 h compared to that in untreated cells (Fig. 3A). Similarly, aLTA treatment following anti-IFN-γ receptor antibody treatment increased cell viability, which was decreased by aLTA only (Fig. 3B). Next, the effects of recombinant proteins for TNF-α and IFN-γ on THP-1 cell viability were assessed. Cytokine-only treatment slightly decreased cell viability, while combination treatment of TNF-α and IFN-γ significantly decreased cell viability, indicating that expressed TNF-α and IFN-γ from aLTAtreated THP-1 cells induce apoptosis through an autocrine function (Fig. 3C).

Figure 3.TNF-α and IFN-γ induced THP-1 apoptosis. (A) THP-1 cells were pretreated with anti-TNFRII antibody for 30 min and then treated with 100 μg/ml LTA for indicated times. (B) THP-1 cells were pretreated with anti-IFN-γR antibody for 30 min and then treated with 100 μg/ml LTA for indicated times. (C) THP-1 cells were treated with recombinant human TNF-α and IFN-γ for 24 h. Cell viability was examined by WST-1 assay. Data are displayed as mean ± SD of three independent experiments. For (A) and (B), statistical analysis was conducted with one-way ANOVA and Tukey’s statistical test. **p < 0.01; ***p < 0.001 compared to None. For (C), statistical analysis was conducted with unpaired two-tailed t test. ***p < 0.001.

SOCS-1-mediated Bcl2 inhibition plays an important role in aLTA-mediated THP-1 apoptosis

Unlike caspase genes, Bcl2 was not altered by aLTA. However, Bcl2 was diminished by LTA in a time-dependent manner (Fig. 4A), suggesting that another regulatory mechanism exists in aLTA-treated conditions. Thus, the role of negative regulators in aLTA-mediated Bcl2 inhibition was examined. siRNA transfected THP-1 cells were treated with 100 μg/ml aLTA for 6 h, and the expression of Bcl2 mRNA was examined by real-time PCR (Fig. 4B). Bcl2 mRNA was reduced by aLTA in control siRNA-transfected THP-1 cells, and the level of Bcl2 was restored in siSOCS-1 RNA-transfected cells. These results suggest that SOCS-1 inhibits the aLTAmediated signaling pathway for Bcl2 expression. The Bcl2 protein level was increased in siSOCS-1 transfected cells (Fig. 4C, lower panel), while it was reduced by aLTA in normal THP-1 cells (Fig. 4C, upper panel). The effect of siRNA on SOCS-1 was examined by western blotting, as shown in the lower panel. Other negative regulators, such as A20 and Abin-1, did not affect Bcl2 expression.

Figure 4.SOCS-1 mediated LTA-mediated Bcl2 reduction. (A) THp-1 cells were treated with 100 μg/ml LTA for indicated times. mRNA level of Bcl2 was examined by real-time PCR. (B) THP-1 cells were transiently transfected with siRNAs for negative regulators of A20, Abin-1, CYLD, IRAK-M, SOCS-1, and SOCS-3. Transfectants were treated with 100 μg/ml LTA for 6 h. mRNA level of Bcl2 was examined by real-time PCR. (C) THP-1 cells were treated with 50 or 100 μg/ml LTA for 6 h, and Bcl2 protein level was examined by western blot (upper panel). THP-1 cells were transiently transfected with siRNA for A20, Abin-1, or SOCS-1 and treated with 100 μg/ml LTA for 6 h. Bcl2 and SOCS-1 protein levels were examined by western blot. β-actin was used as loading control. (D) THP-1 cells transfected with siCtr or siSOCS-1 were stimulated with aLTA for 48 h. Cell viability was examined by WST-1 assay. Statistical analysis was conducted with an unpaired two-tailed t test. *p < 0.05; **p < 0.01; ***p < 0.001 compared to 0 h or None.

Our data elucidated that TNF-α and IFN-γ produced from aLTA-treated THP-1 cells induced cell apoptosis through autocrine stimulation, which was confirmed using neutralization antibodies for TNFRII and IFNαR. Combination treatment of recombinant human TNF-α and IFN-γ proteins also induced THP-1 apoptosis, while individual treatment did not induce significant cell death (Fig. 3). TNF-α, a pro-inflammatory cytokine, is secreted by inflammatory cells and plays important roles in cell survival, proliferation, and death. TNF-α can stimulate cancer cell growth and has the potential to stimulate cancer cell death [12].

IFN-γ, which is predominantly produced by T cells and NK cells, is involved in tumor immune surveillance and immune evasion [13]. Interestingly, combination treatment of TNF-α and IFN-γ has a synergistic effect on cancer therapy. Combination treatment of TNF-α and IFN-γ induced apoptosis and necrosis of several carcinoma cells, including bone marrow mesenchymal stem cells (BMMSCs), ME-180 cervical cancer cells, NIT-1 insulinoma cells, and oligodendroglial cell lines [14-17]. However, combination treatment of TNF-α and IFN-γ seems to induce normal cell death as well. The viability of primary pancreatic β cells was decreased by TNF-α and IFN-γ treatment [16]. Apoptosis of vascular smooth muscle cells and spinal cord embryonic explants was also induced by in vitro stimulation with the two cytokines [18, 19]. Although combination treatment of TNF- α and IFN-γ significantly increased the cytotoxicity of cancer cells, re-growth of cancer cells was shown after 3 days of exposure of human colon carcinoma cell lines to TNF-α and IFN-γ. This suggests that combination therapy using TNF-α and IFN-γ was limited for removing cancer [20].

Although TNF-α has been considered a potential anticancer agent, it is not attractive as a systemic drug due to its toxicity and low efficiency to the human body. rhTNF-α showed a reduction in the maximum tolerated dose (MTD) when used in combination with other cytokines such as IL-2 and IFN-γ in phase 1 clinical trial for solid tumor patients. However, this result is considered to have been caused by the redundant toxicity of the cytokine used in the test. Due to toxicity and inefficiencies of testing with various cytokine combinations in the initial trial, no additional secondary clinical trials were conducted [21]. The current study showed that LTA from gram-positive bacteria can induce pro-inflammatory cytokines such as TNF-α and IFN-γ, which induce cell death. Although our data suggest that aLTA could be an efficacious agent for cancer treatment by inducing TNF-α and IFN-γ from immune cells, further study is needed to reduce cytotoxicity against normal cells.

During infection, S. aureus induces apoptosis in a wide range of target cells as a means of invading tissues and antagonizing host immune defenses [22]. Cell death, such as apoptosis and necrosis, is also used when S. aureus is released from keratinocytes [23]. S. aureus produces apoptotic virulence factors, including potent toxins such as α-toxin and enterotoxins and superantigens [22]. In addition to endotoxins and exotoxins, aLTA seems to be able to induce host cell apoptosis. aLTAmediated apoptosis was mediated by Bcl2 inhibition as well as Caspase 3 activation. Bcl2 mRNA production of THP-1 cells was significantly decreased by 3 h of aLTA treatment. Unfortunately, there is no report indicating how aLTA regulates Bcl2 production. In this study, we examined the role of negative regulators on aLTA-mediated Bcl2 regulation. When negative regulators were knocked down using siRNA, aLTA-mediated Bcl2 production was increased by siSOCS-1 RNA. This result suggests that SOCS-1 may regulate Bcl2 production in aLTA-treated THP-1 cells. Negative regulators including A20, Abin-1, CYLD, IRAK-M, SOCS-1, and SOCS-3 inhibit the signaling pathways involved in cytokine production. Among these, SOCS-1 negatively regulates the JAK/STAT pathway [24]. TLR ligands including aLTA induce SOCS-1 production directly through activation of early growth response-1 (EGR-1) and/or indirectly through cytokines, including IL-6 and IFN-β, induced by initial TLR signaling [25, 26]. Fujimoto and Naka proposed inhibitory mechanisms of SOCS-1 on TLR signaling: (i) SOCS-1 binds to Mal/TIRAP and mediates its degradation via a proteasomal pathway; (ii) SOCS-1 binds to IRAK and may modulate its activity; (iii) SOCS-1 binds to the p65 subunit of NF-κB and targets it for proteasomal degradation; (iv) SOCS-1 inhibits JAK2 activated directly after TLR stimulation; and (v) SOCS-1 regulates TLR-mediated response indirectly by inhibiting TLR-induced cytokines such as IFN-β [27]. aLTA induces serial activation of signaling pathways, including those of IRAK, NF-κB, and MAPK, to induce pro-inflammatory cytokines. As a feedback inhibition mechanism, aLTA may induce SOCS-1 to inhibit activated signaling pathways. Conversely, Caspase 1 was significantly increased by aLTA, although it was not involved in aLTA-mediated THP-1 cell apoptosis. This suggests that caspase and Bcl2 gene regulation are differently controlled in THP-1 cells after aLTA stimulation.

In conclusion, we found that host cell apoptosis could be induced by aLTA as well as toxins produced by S. aureus. Our study demonstrated that aLTA-induced apoptosis requires cytokines such as TNF-α and IFN-γ. aLTA was involved in cell apoptosis by inhibiting Bcl2 through increased expression of SOCS-1. The present study provides useful preliminary data for the mechanism study of host ceall apoptosis using aLTA, a cell wall component of S. aureus.

This work was supported by a grant from Kyung Hee University in 2020 (KHU-20202190).

The authors have no financial conflicts of interest to declare.

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