IFN-γ regulation of class II transactivator promoter IV in macrophages and microglia: Involvement of the suppressors of cytokine signaling-1 protein

Academic Article

Abstract

  • The discovery of the class II transactivator (CIITA) transcription factor, and its IFN-γ-activated promoter (promoter IV), have provided new opportunities to understand the molecular mechanisms of IFN-γ-induced class II MHC expression. Here, we investigated the molecular regulation of IFN-γ-induced murine CIITA promoter IV activity in microglia/macrophages. In the macrophage cell line RAW264.7, IFN-γ inducibility of CIITA promoter IV is dependent on an IFN-γ activation sequence (GAS) element and adjacent E-Box, and an IFN response factor (IRF) element, all within 196 bp of the transcription start site. In both RAW cells and the microglia cell line EOC20, two IFN-γ-activated transcription factors, STAT-1α and IRF-1, bind the GAS and IRF elements, respectively. The E-Box binds upstream stimulating factor-1 (USF-1), a constitutively expressed transcription factor. Functionally, the GAS, E-Box, and IRF elements are each essential for IFN-γ-induced CIITA promoter IV activity. The effects of the suppressors of cytokine signaling-1 (SOCS-1) protein on IFN-γ-induced CIITA and class II MHC expression were examined. Ectopic expression of SOCS-1 inhibits IFN-γ-induced activation of CIITA promoter IV and subsequent class II MHC protein expression. Interestingly, SOCS-1 inhibits the constitutive expression of STAT-1α and its IFN-γ-induced tyrosine phosphorylation and binding to the GAS element in CIITA promoter IV. As well, IFN-γ-induced expression of IRF-1 and its binding to the IRF element is inhibited. These results indicate that SOCS-1 may be responsible for attenuating IFN-γ-induced CIITA and class II MHC expression in macrophages.
  • Published In

    Digital Object Identifier (doi)

    Author List

  • O'Keefe GM; Nguyen VT; Li Ping Tang; Benveniste EN
  • Start Page

  • 2260
  • End Page

  • 2269
  • Volume

  • 166
  • Issue

  • 4