Aberrant Toll-like receptor 2 promoter methylation in blood cells from patients with pulmonary tuberculosis - 18/11/14

Doi : 10.1016/j.jinf.2014.08.014

Yung-Che Chen ^a,^e , Chang-Chun Hsiao ^e,^⁎ , Chung-Jen Chen ^b , Tung-Ying Chao ^a , Sum-Yee Leung ^a , Shih-Feng Liu ^a,^c , Chin-Chou Wang ^a , Ting-Ya Wang ^a , Jen-Chieh Chang ^d , Chao-Chien Wu ^a , An-Shen Lin ^a , Yi-Hsi Wang ^a , Meng-Chih Lin ^a,^⁎
^a Division of Pulmonary and Critical Care Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan, ROC
^b Division of Rheumatology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan, ROC
^c Department of Respiratory Therapy, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan, ROC
^d Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan, ROC
^e Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Taiwan, ROC

^∗Corresponding author. Division of Pulmonary and Critical Care Medicine, Department of Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123, Ta-Pei Rd, Niao-Sung District, Kaohsiung City, Taiwan, ROC. Tel.: +886 7 7317123x8199; fax: +886 7 7322402.^∗∗Corresponding author.

Summary

Objectives

Toll-like receptor 2 (TLR2) is a major mediator of innate immunity against tuberculosis (TB). This study aimed to determine if TLR2 promoter DNA methylation is associated with pulmonary TB.

Methods

The DNA methylation levels of 20 CpG sites over the TLR2 promoter region and TLR2 gene/protein expressions of immune cells of the blood were examined in 99 sputum culture-positive pulmonary TB patients and 77 healthy subjects (HS).

Results

TB patients had higher methylation levels over five CpG sites (3, 7, 9, 13, and 18), lower TLR2 gene expression, lower TLR2 expression on monocyte, higher TLR2 expression on NK cell, and higher serum TNF-α/IFN-γ levels than HS after adjusting for confounding factors. Patients with a high bacillary load had lower methylation levels at CpG-15, -17, and -20. Patients with drug-resistant TB had higher CpG-18 methylation levels and lower TLR2 expression on NK cell. Patients with far advanced lesion on chest radiograph had higher serum TNF-α level and higher TLR2 expression on NK cell. Patients with a high TLR2 expression on NK cell had lower one-year survival. CpG-18 methylation level, TLR2 expressions on monocyte/NK cell, and TNF-α/IFN-γ levels were all reversed to normal after 6-month anti-TB treatment.

Conclusions

Aberrant methylation of certain CpG sites over TLR2 promoter region is associated with active pulmonary TB or its phenotypes, probably through the down-regulation of TLR2 expression.

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Highlights

•	Five CpG sites of the TLR2 promoter region are hyper-methylated in TB patients.
•	DNA methylation level at CpG-18 is further increased in drug-resistant TB.
•	Pulmonary TB patients have lower TLR2 expression on blood monocyte.
•	Pulmonary TB patients have higher TLR2 expression on blood NK cell.
•	CpG-18 methylation and TLR2 expressions are reversed after anti-TB treatment.

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Keywords : Toll-like receptor 2, DNA methylation, Pulmonary tuberculosis, Monocyte, Natural killer cell

Plan

Introduction

Patients and methods

Study subjects

Measurement of DNA methylation levels over TLR2 promoter region by bisulfite pyrosequencing method

Measurement of TLR2 mRNA gene expressions of peripheral blood leukocytes by quantitative real-time reverse transcription (RT)-PCR method

Measurement of TLR2 protein expressions on the cell surface of peripheral blood CD14⁺monocytes, CD3⁺CD56⁺ NK T cell, CD3⁺CD56⁻ T cell, and CD3⁻CD56⁺NK cells by flow cytometry

Measurement of TLR2 total protein expression of leukocytes by Western blot

Measurements of serum cytokine levels

Statistical analysis

Results

Demographic data of the participants

Comparisons of TLR2 promoter methylation levels, TLR2 gene expression, and TLR2 protein expressions between TB patients and healthy subjects

Comparisons of TLR2 promoter DNA methylation levels, TLR2 gene expression, and TLR2 protein expressions among various pulmonary TB phenotypes

Changes in TLR2 promoter DNA methylation levels, TLR2 gene expression, and TLR2 protein expressions after 6-month anti-TB treatment

Discussion

List of abbreviations

Authors' contributions

Conflict of interests

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Vol 69 - N° 6

P. 546-557 - décembre 2014 Retour au numéro

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Aberrant Toll-like receptor 2 promoter methylation in blood cells from patients with pulmonary tuberculosis - 18/11/14

Summary

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