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Activation of the JAK/STAT-1 signaling pathway by IFN-gamma can down-regulate functional expression of the MHC class I-related neonatal Fc receptor for IgG.

Expression of many MHC genes is enhanced at the transcriptional or posttranscriptional level following exposure to the cytokine IFN-gamma. However, in this study we found that IFN-gamma down-regulated the constitutive expression of the neonatal Fc receptor (FcRn), an MHC class I-related molecule that functions to transport maternal IgG and protect IgG and albumin from degradation. Epithelial cell, macrophage-like THP-1 cell, and freshly isolated human PBMC exposure to IFN-gamma resulted in a significant decrease of FcRn expression as assessed by real-time RT-PCR and Western blotting. The down-regulation of FcRn was not caused by apoptosis or the instability of FcRn mRNA. Chromatin immunoprecipitation and gel mobility shift assays showed that STAT-1 bound to an IFN-gamma activation site in the human FcRn promoter region. Luciferase expression from an FcRn promoter-luciferase reporter gene construct was not altered in JAK1- and STAT-1-deficient cells following exposure to IFN-gamma, whereas expression of JAK1 or STAT-1 protein restored the IFN-gamma inhibitory effect on luciferase activity. The repressive effect of IFN-gamma on the FcRn promoter was selectively reversed or blocked by mutations of the core nucleotides in the IFN-gamma activation site sequence and by overexpression of the STAT-1 inhibitor PIAS1 or the dominant negative phospho-STAT-1 mutations at Tyr-701 and/or Ser-727 residues. Furthermore, STAT-1 might down-regulate FcRn transcription through sequestering the transcriptional coactivator CREB binding protein/p300. Functionally, IFN-gamma stimulation dampened bidirectional transport of IgG across a polarized Calu-3 lung epithelial monolayer. Taken together, our results indicate that the JAK/STAT-1 signaling pathway was necessary and sufficient to mediate the down-regulation of FcRn gene expression by IFN-gamma.

Pubmed ID: 18566411

Authors

  • Liu X
  • Ye L
  • Bai Y
  • Mojidi H
  • Simister NE
  • Zhu X

Journal

Journal of immunology (Baltimore, Md. : 1950)

Publication Data

July 1, 2008

Associated Grants

  • Agency: NIAID NIH HHS, Id: AI65892
  • Agency: NIAID NIH HHS, Id: AI67965
  • Agency: NIAID NIH HHS, Id: AI73139
  • Agency: NIAID NIH HHS, Id: R01 AI065892
  • Agency: NIAID NIH HHS, Id: R01 AI065892-02
  • Agency: NIAID NIH HHS, Id: R21 AI067965
  • Agency: NIAID NIH HHS, Id: R21 AI067965-02
  • Agency: NIAID NIH HHS, Id: R21 AI073139
  • Agency: NIAID NIH HHS, Id: R21 AI073139-02

Mesh Terms

  • Animals
  • Apoptosis
  • Binding Sites
  • Cell Line
  • Down-Regulation
  • Enzyme Activation
  • Gene Expression Regulation
  • Histocompatibility Antigens Class I
  • Humans
  • Immunoglobulin G
  • Interferon-gamma
  • Janus Kinase 1
  • Lung
  • Phosphorylation
  • Promoter Regions, Genetic
  • Protein Transport
  • RNA, Messenger
  • Receptors, Fc
  • STAT1 Transcription Factor
  • Signal Transduction
  • Transcription, Genetic