title: Regulatory mechanism of TNFalpha autoregulation in HaCaT cells: the role of the transcription factor EGR-1.
abstract: Tumor necrosis factor alpha (TNFalpha) is a pro-inflammatory cytokine involved in innate immune response, as well as in the pathogenesis of many inflammatory diseases. Although several response elements in the TNFalpha promoter region are involved in the activation of gene transcription, few studies have examined the regulatory mechanism that controls TNFalpha autoregulation. In this study, we investigated the role of the Early Growth Response-1 (EGR-1) transcription factor in TNFalpha autoregulation in HaCaT human keratinocytes. The requirement for EGR-1 in TNFalpha autoregulation was confirmed using a construct harboring a point mutation in the EGR-1 binding site within the TNFalpha promoter and the introduction of EGR-1 siRNA. Inhibition of the ERK or JNK pathway suppressed TNFalpha-induced EGR-1 expression, resulting in the inhibition of TNFalpha-induced TNFalpha promoter activation. These results reveal that the ERK and JNK MAPK pathways contribute to the autoregulation of TNFalpha synthesis via EGR-1 induction in HaCaT keratinocytes.
authors.affiliation: Department of Dermatology, Korea University College of Medicine, Seoul 136-301, Republic of Korea.
authors.forename: Sang Wook
authors.initials: SW
authors.lastname: Son
authors.forename: Byong Wook
authors.initials: BW
authors.lastname: Min
authors.forename: Yoongho
authors.initials: Y
authors.lastname: Lim
authors.forename: Young Han
authors.initials: YH
authors.lastname: Lee
authors.forename: Soon Young
authors.initials: SY
authors.lastname: Shin
mesh_terms: D001665:Binding Sites; D002460:Cell Line; D051766:Early Growth Response Protein 1 / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006706:Homeostasis / Q000235:genetics*; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D017354:Point Mutation; D011401:Promoter Regions, Genetic; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
chemical_list: C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D014409:Tumor Necrosis Factor-alpha; D048049:Extracellular Signal-Regulated MAP Kinases; D048670:MAP Kinase Kinase 4