title: Aberrant Toll-like receptor 2 promoter methylation in blood cells from patients with pulmonary tuberculosis.
abstract: OBJECTIVE
  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.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan, ROC; Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Taiwan, ROC. Electronic address: yungchechen@yahoo.com.tw.
authors.forename: Yung-Che
authors.initials: YC
authors.lastname: Chen
authors.affiliation: Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Taiwan, ROC. Electronic address: cchsiao@mail.cgu.edu.tw.
authors.forename: Chang-Chun
authors.initials: CC
authors.lastname: Hsiao
authors.affiliation: Division of Rheumatology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan, ROC. Electronic address: chungjencgmh@gmail.com.
authors.forename: Chung-Jen
authors.initials: CJ
authors.lastname: Chen
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan, ROC. Electronic address: tychao@adm.cgmh.org.tw.
authors.forename: Tung-Ying
authors.initials: TY
authors.lastname: Chao
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan, ROC. Electronic address: sumyeeleung@hotmail.com.
authors.forename: Sum-Yee
authors.initials: SY
authors.lastname: Leung
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan, ROC; Department of Respiratory Therapy, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan, ROC. Electronic address: m85d@adm.cgmh.org.tw.
authors.forename: Shih-Feng
authors.initials: SF
authors.lastname: Liu
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan, ROC. Electronic address: ccwang5202@yahoo.com.tw.
authors.forename: Chin-Chou
authors.initials: CC
authors.lastname: Wang
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan, ROC. Electronic address: filling.tw@yahoo.com.tw.
authors.forename: Ting-Ya
authors.initials: TY
authors.lastname: Wang
authors.affiliation: Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan, ROC. Electronic address: gpc.cgmh@gmail.com.
authors.forename: Jen-Chieh
authors.initials: JC
authors.lastname: Chang
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan, ROC. Electronic address: my47104710@gmail.com.
authors.forename: Chao-Chien
authors.initials: CC
authors.lastname: Wu
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan, ROC. Electronic address: anshen@adm.cgmh.org.tw.
authors.forename: An-Shen
authors.initials: AS
authors.lastname: Lin
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan, ROC. Electronic address: yihsi@adm.cgmh.org.tw.
authors.forename: Yi-Hsi
authors.initials: YH
authors.lastname: Wang
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan, ROC. Electronic address: mengchihlin@yahoo.com.tw.
authors.forename: Meng-Chih
authors.initials: MC
authors.lastname: Lin
mesh_terms: D000328:Adult; D000368:Aged; D001483:Base Sequence; D016022:Case-Control Studies; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007371:Interferon-gamma / Q000097:blood; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009000:Monocytes / Q000276:immunology / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051195:Toll-Like Receptor 2 / Q000235:genetics* / Q000378:metabolism; D018088:Tuberculosis, Multidrug-Resistant / Q000235:genetics; D014397:Tuberculosis, Pulmonary / Q000235:genetics / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma
keywords: DNA methylation; Monocyte; Natural killer cell; Pulmonary tuberculosis; Toll-like receptor 2