title: High levels of tumor necrosis factor-α downregulate antimicrobial iron transport protein, Nramp1, in chronic hemodialysis patients: a key factor for infection risk.
abstract: OBJECTIVE
  The susceptibility of patients on maintenance hemodialysis (MHD) to infections is a major cause of mortality and morbidity. Natural resistance-associated macrophage protein 1 (Nramp1) regulates intracellular pathogen proliferation, and its mRNA expression is highest in polymorphonuclear leukocytes (PMNLs). The purpose of this study was to determine the level of Nramp1 in PMNLs from MHD patients and the factors affecting its expression.
  
  
  METHODS
  Twenty MHD patients and 24 healthy volunteers (controls) were recruited. Relative quantitative PCR was used to measure Nramp1 mRNA, and protein levels were semiquantified by means of real-time PCR and Western blot analysis or immunohistochemistry. The effect of tumor necrosis factor-α (TNF-α) or interleukin-6 (IL-6) on Nramp1 expression in PMNLs from controls was also examined.
  
  
  RESULTS
  Nramp1 mRNA and protein levels were substantially lower in PMNLs from MHD than control subjects. Serum TNF-α levels were significantly higher in the MHD group and were inversely correlated with Nramp1 mRNA levels. The addition of TNF-α to PMNLs from control subjects decreased mRNA and protein levels of Nramp1. IL-6 did not alter Nramp1 mRNA or protein expression.
  
  
  CONCLUSIONS
  We found that Nramp1 was downregulated in the PMNLs of MHD patients, which constitute the first defense barrier against bacterial challenges. High levels of TNF-α may be associated with the downregulation of Nramp1. Our findings indicate that the susceptibility to infection observed in MHD patients could be partly due to the impairment of the intracellular handling of iron and the donation of more iron to the bacteria.
authors.affiliation: Division of Kidney and Dialysis, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan.
authors.forename: Rintarou
authors.initials: R
authors.lastname: Moriguchi
authors.forename: Yoshinaga
authors.initials: Y
authors.lastname: Otaki
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hazeki
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Shimada
authors.forename: Ayako
authors.initials: A
authors.lastname: Matsumoto
authors.forename: Naoto
authors.initials: N
authors.lastname: Kakita
authors.forename: Shoji
authors.initials: S
authors.lastname: Kaibe
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kuragano
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nonoguchi
authors.forename: Nanami
authors.initials: N
authors.lastname: Masayoshi
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Hasuike
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nakanishi
mesh_terms: D000368:Aged; D027682:Cation Transport Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D015536:Down-Regulation; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000097:blood / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D006435:Renal Dialysis; D051436:Renal Insufficiency, Chronic / Q000097:blood* / Q000628:therapy; D014409:Tumor Necrosis Factor-alpha / Q000097:blood* / Q000494:pharmacology; D000099173:Natural Resistance-associated Macrophage Protein 1
chemical_list: D027682:Cation Transport Proteins; D015850:Interleukin-6; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000099173:Natural Resistance-associated Macrophage Protein 1