IFN-gamma regulation of class II transactivator promoter IV in macrophagesand microglia: Involvement of the suppressors of cytokine signaling-1 protein
Gm. O'Keefe et al., IFN-gamma regulation of class II transactivator promoter IV in macrophagesand microglia: Involvement of the suppressors of cytokine signaling-1 protein, J IMMUNOL, 166(4), 2001, pp. 2260-2269
The discovery of the class II transactivator (CIITA) transcription factor,
and its IFN-gamma -activated promoter (promoter IV), have provided new oppo
rtunities to understand the molecular mechanisms of IFN-gamma -induced clas
s II MHC expression. Here, we investigated the molecular regulation of IFN-
gamma -induced murine CIITA promoter IV activity in microglia/macrophages.
In the macrophage tell line RAW261.7, IFN-gamma inducibility of CIITA promo
ter IV is dependent on an IFN-gamma activation sequence (GAS) element and a
djacent 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 l
ine EOC20, two IFN-gamma -activated transcription factors, STAT-1 alpha and
IRF-1, bind the GAS and IRF elements, respectively. The E-Box binds upstre
am stimulating factor-1 (USF-1), a constitutively expressed transcription f
actor. Functionally, the GAS, E-Box, and IRF elements are each essential fo
r IFN-gamma -induced CIITA promoter IV activity. The effects of the suppres
sors of cytokine signaling-1 (SOCS-1) protein an IFN-gamma -induced CIITA a
nd class II MHC expression were examined. Ectopic expression of SOCS-1 inhi
bits IFN-gamma -induced activation of CIITA promoter IV and subsequent clas
s II MHC protein expression. Interestingly, SOCS-1 inhibits the constitutiv
e expression of STAT-1 alpha and its IFN-gamma -induced tyrosine phosphoryl
ation and binding to the GAS element in CIITA promoter IV. AS well, IFN-gam
ma -induced expression of IRE-I and its binding to the IRF element is inhib
ited. These results indicate that SOCS-1 may be responsible for attenuating
IFN-gamma -induced CIITA and class II MBC expression in macrophages.