IgG immune complexes inhibit IFN-gamma-induced transcription of the Fc gamma RI gene in human monocytes by preventing the tyrosine phosphorylation of the p91 (Stat1) transcription factor.
Immune complexes (IC) modulate Ag-driven immune responses in part by their ability to inhibit IFN-gamma-dependent MHC class II expression. Because many genes, including MHC class II Ags, transcriptionally activated by IFN-gamma require the tyrosine phosphorylation of the transcription factor p91 (Stat1), we examined whether IC could suppress IFN-gamma-induced expression of the Fc gamma receptor I gene (Fc gamma RI) in human monocytes and whether this occurred through inhibition of p91 phosphorylation. Preincubation of monocytes on gamma-globulin-coated dishes resulted in a 80% reduction in steady state levels of RNA for the Fc gamma RI gene. Nuclear run-on analysis confirmed that the inhibition was at the level of transcription. Treatment with IC resulted in no change in the IFN-gamma receptor number. In monocytes pretreated with IC, there was a 79% reduction in the formation of FcRF gamma, a p91-containing DNA binding protein complex that is rapidly activated by IFN-gamma, and which recognizes the gamma response region enhancer within the promoter of the Fc gamma RI gene. Furthermore, there was a marked reduction in the tyrosine phosphorylation of p91. Pretreatment with IC resulted in the inhibition of the tyrosine phosphorylation of the tyrosine kinases, Jak1 and Jak2, both of which are involved in IFN-gamma signal transduction. Therefore, culture of monocytes on IC inhibits IFN-gamma-induced expression of the Fc gamma RI gene by preventing tyrosine phosphorylation of p91, probably by the associated inhibition of the tyrosine kinases Jak1 and Jak2.
Feldman
G M
GM
Food and Drug Administration, Division of Cytokine Biology, Bethesda, MD 20892.
Chuang
E J
EJ
Finbloom
D S
DS
D000936:Antigen-Antibody Complex / Q000276:immunology*; D001483:Base Sequence; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation; D005786:Gene Expression Regulation; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors*; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D008969:Molecular Sequence Data; D009000:Monocytes / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D017452:Receptors, IgG / Q000096:biosynthesis* / Q000235:genetics; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic
D000936:Antigen-Antibody Complex; D004268:DNA-Binding Proteins; D007074:Immunoglobulin G; D011518:Proto-Oncogene Proteins; D017452:Receptors, IgG; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507924:JAK2 protein, human; D053613:Janus Kinase 1; D053614:Janus Kinase 2