title: ATF3 confers resistance to pneumococcal infection through positive regulation of cytokine production.
abstract: BACKGROUND
  Activating transcription factor-3 (ATF3) is known as a suppressor of cytokine production after exposure to lipopolysaccharide or during gram-negative bacterial infection. However, the mechanism by which ATF3 regulates innate immunity against gram-positive bacterial infection, particularly Streptococcus pneumoniae, remains unknown.
  
  
  METHODS
  The wild-type and ATF3 knock-out (KO) mice were infected intranasally (i.n) or intraperitoneally with S. pneumoniae, and bacterial colonization or survival rate was determined. Pneumococcal pneumonia was induced by i.n infection, and ATF3 level was determined by Western blot. ATF3 KO cells or ATF3 siRNA transfection were used to determine expression of ATF3 downstream genes. Enzyme-linked immunosorbent assay was used to examine cytokines levels.
  
  
  RESULTS
  ATF3 was highly expressed in various cell lines in vitro and in many organs in vivo. Pneumolysin was a novel inducer of ATF3. Pneumococcal infection induced ATF3, which subsequently stimulated production of cytokines (tumor necrosis factor [TNF]-α, interleukin [IL]-1β, and interferon [IFN]-γ). ATF3-mediated cytokine induction protected the host from pneumococcal infection. In the pneumonia infection model, the bacterial clearance of wild-type mice was more efficient than those of ATF3 KO mice.
  
  
  CONCLUSIONS
  Taken together, we can conclude that ATF3 regulates innate immunity positively upon pneumococcus infection by enhancing TNF-α, IL-1β, and IFN-γ expression and modulating bacterial clearance.
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Su-Won, South Korea.
authors.forename: Cuong Thach
authors.initials: CT
authors.lastname: Nguyen
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Su-Won, South Korea.
authors.forename: Eun-Hye
authors.initials: EH
authors.lastname: Kim
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Su-Won, South Korea.
authors.forename: Truc Thanh
authors.initials: TT
authors.lastname: Luong
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Su-Won, South Korea.
authors.forename: Suhkneung
authors.initials: S
authors.lastname: Pyo
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Su-Won, South Korea.
authors.forename: Dong-Kwon
authors.initials: DK
authors.lastname: Rhee
mesh_terms: D051700:Activating Transcription Factor 3 / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D004195:Disease Models, Animal; D060467:Disease Resistance / Q000235:genetics* / Q000276:immunology; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D051379:Mice; D018345:Mice, Knockout; D011008:Pneumococcal Infections / Q000235:genetics* / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology / Q000401:mortality; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D013296:Streptococcus pneumoniae / Q000276:immunology / Q000378:metabolism; D013301:Streptolysins / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D051700:Activating Transcription Factor 3; D001426:Bacterial Proteins; D016207:Cytokines; D013301:Streptolysins; D014409:Tumor Necrosis Factor-alpha; C032290:plY protein, Streptococcus pneumoniae
keywords: IFN-γ; IL-1β; S. pneumoniae; TNF-α; activating transcription factor (ATF3); pneumococcal infection; pneumonia