Block of Stat-1 activation in macrophages phagocytosing bacteria causes reduced transcription of CIITA and consequent impaired antigen presentation.
The IFN-gamma-induced HLA class II expression in human macrophages was drastically reduced after phagocytosis of Escherichia coli. HLA class II down-modulation depended on phagocytosis of bacteria and could not be reproduced by phagocytosis of inert particles or by treatment with lipopolysaccharide. Study of the kinetics and molecular analysis showed that class II molecules and corresponding mRNA were up-regulated at 6 h after phagocytosis of bacteria. Subsequently, a progressive reduction of mRNA occurred, and, at 72 h, as little as 25% of the class II mRNA level of IFN-gamma-treated control cells was found. This was due to reduced transcription of the class II transcriptional activator CIITA, as a consequence of reduced immediate-early inducible factor (IRF-1) and particularly of reduced phosphorylated Stat-1 homodimers, nuclear factors both necessary for optimal triggering of the CIITA promoter. Failure to sustain IFN-gamma-induced CIITA up-modulation during phagocytosis of bacteria had functional implications, as human macrophages could not adequately process and present antigenic peptides to HLA-DR-restricted antigen-specific T cells. This is the first evidence that phagocytosis of bacteria can down-modulate HLA class II expression in normal human macrophages by acting at the level of expression of CIITA.
Barbaro
Andrea De Lerma
Ade L
Department of Clinical and Biological Sciences, School of Medicine, University of Insubria, Varese, Italy.
Tosi
Giovanna
G
Frumento
Guido
G
Bruschi
Emanuele
E
D'Agostino
Antonella
A
Valle
Maria-Teresa
MT
Manca
Fabrizio
F
Accolla
Roberto S
RS
D017951:Antigen Presentation; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D019281:Dimerization; D015536:Down-Regulation; D004926:Escherichia coli / Q000276:immunology; D005802:Genes, MHC Class II; D006684:HLA-DR Antigens / Q000235:genetics / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D050856:Interferon Regulatory Factor-1; D007371:Interferon-gamma / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D009687:Nuclear Proteins; D010587:Phagocytosis / Q000276:immunology*; D010750:Phosphoproteins / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; D015534:Trans-Activators / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; D006684:HLA-DR Antigens; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D007371:Interferon-gamma