Protein inhibitor of activated signal transducer and activator of transcription (STAT)-1 (PIAS-1) regulates the IFN-gamma response in macrophage cell lines.
Macrophage cell lines exhibit different responses to IFN-gamma depending on their maturation stage. We investigated the mechanisms underlying the differential IFN-gamma responsiveness in the less mature P388.D1 and in mature RAW264.7 cells. A reduction in the binding activity of the signal transducer and activator of transcription-1 (STAT-1) to different STAT binding elements (SBEs) was observed in P388.D1. This reduced binding activity was not due to an impaired STAT-1 activation. Studies on the expression of a negative regulator of cytokine signalling, protein-inhibiting activated STAT-1 (PIAS-1), showed that this protein was expressed constitutively at high levels in P388.D1. Forced expression of a PIAS-1 homologue, the Gu binding protein (GBP), inhibited the STAT-1-mediated gene activation in RAW264.7 cells, whereas a construct expressing the 5' portion of GBP in the antisense orientation reverts the IFN-gamma-resistant phenotype of P388.D1. Thus, our results indicate that PIAS-1 may account for the differential IFN-gamma responsiveness in macrophage cell lines at different stages of maturation.
Coccia
Eliana M
EM
Laboratory of Immunology, Viale Regina Elena 299, 00161 Rome, Italy. e.coccia@iss.it
Stellacci
Emilia
E
Orsatti
Roberto
R
Benedetti
Eleonora
E
Giacomini
Elena
E
Marziali
Giovanna
G
Valdez
Benigno C
BC
Battistini
Angela
A
D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D016373:DNA, Antisense / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D050828:Protein Inhibitors of Activated STAT; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D050794:STAT1 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000378:metabolism
D016373:DNA, Antisense; D004268:DNA-Binding Proteins; C494211:Pias1 protein, mouse; D050828:Protein Inhibitors of Activated STAT; D011506:Proteins; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D007371:Interferon-gamma