title: ATF3 plays a key role in Kdo2-lipid A-induced TLR4-dependent gene expression via NF-κB activation.
abstract: BACKGROUND
  Activating transcription factor 3 (ATF3) is a negative regulator of proinflammatory cytokine expression in macrophages, and ATF3 deficient mice are more susceptible to endotoxic shock. This study addresses the role of ATF3 in the Kdo(2)-Lipid A-induced Toll-like receptor 4 (TLR4) signaling pathway in mouse embryonic fibroblasts (MEF). Kdo(2)-Lipid A upregulates ATF3 expression in wild type MEF cells and induces both nuclear factor kappa B (NF-κB) and c-Jun N-terminal kinase (JNK) activation via the TLR4 signaling pathway, while neither of these pathways is activated in ATF3-/- MEF cells. Interestingly, in contrast to Kdo(2)-Lipid A, the activation of both NF-κB and JNK by TNF-α was normal in ATF3-/- MEF cells.
  
  
  RESULTS
  We found that several genes were dramatically upregulated in ATF3+/+ MEF cells in response to Kdo(2)-Lipid A treatment, while little difference was observed in the ATF3-/- MEF cells. However, we also found that the signal intensities of IκBζ in ATF3-/- MEF cells were substantially higher than those in wild type MEF cells upon microarray analyses, and upregulated IκBζ expression was detected in the cytosol fraction.
  
  
  CONCLUSIONS
  Our findings indicate that ATF3 deficiency affects Kdo(2)-Lipid A-induced TLR4 signaling pathways in MEF cells, that it may upregulate IκBζ expression and that the high levels of IκBζ expression in ATF3-/- cells disrupts Kdo(2)-Lipid A-mediated signaling pathways.
authors.affiliation: Department of Molecular Science and Technology, Ajou University, Suwon, Korea.
authors.forename: Eun-Young
authors.initials: EY
authors.lastname: Kim
authors.forename: Hye Young
authors.initials: HY
authors.lastname: Shin
authors.forename: Joo-Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Dong-Gun
authors.initials: DG
authors.lastname: Kim
authors.forename: Yong-Min
authors.initials: YM
authors.lastname: Choi
authors.forename: Hyuk-Kwon
authors.initials: HK
authors.lastname: Kwon
authors.forename: Dong-Kwon
authors.initials: DK
authors.lastname: Rhee
authors.forename: You-Sun
authors.initials: YS
authors.lastname: Kim
authors.forename: Sangdun
authors.initials: S
authors.lastname: Choi
mesh_terms: D051700:Activating Transcription Factor 3 / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D008050:Lipid A / Q000378:metabolism; D008070:Lipopolysaccharides / Q000737:chemistry*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000737:chemistry*; D014158:Transcription, Genetic
chemical_list: C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; C506188:Kdo2-lipid A; D008050:Lipid A; D008070:Lipopolysaccharides; D016328:NF-kappa B; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D048670:MAP Kinase Kinase 4