Immune complexes suppress IFN-gamma signaling by activation of the FcgammaRI pathway.
Antigen-driven immune responses are modulated by immune complexes (ICs), in part through their ability to inhibit IFN-gamma-dependent MHC Class II expression. We have demonstrated previously that ICs dramatically inhibit IFN-gamma-induced activation of human monocytes through the suppression of the JAK/STAT signaling pathway. In the current study, we further explore the mechanisms by which ICs regulate IFN-gamma activation of human monocytes. Consistent with previous studies in monocytes pretreated with ICs, there was a reduction in steady-state levels of RNA by real-time RT-PCR of the IFN-inducible protein 10 gene as well as the FcgammaRI gene. Pull-down assays confirm that IC pretreatment inhibits IFN-gamma-induced STAT1 phosphorylation without affecting the ability of STAT1 to bind to the STAT1-binding domain of the IFN-gamma receptor. In addition, the inhibitory function of ICs was reduced when cells from the FcR common gamma-chain knockout mice were used, supporting the role of the FcgammaRI in this inhibitory pathway. It is unexpected that ICs also require the phosphatase Src homology-2-containing tyrosine phosphatase 1 (SHP-1) to inhibit IFN-gamma induction, as demonstrated by studies with cells from the SHP-1 knockout (motheaten) mice. These data suggest a mechanism of IC-mediated inhibition of IFN-gamma signaling, which requires the ITAM-containing FcgammaRI, as well as the ITIM-dependent phosphatase SHP-1, ultimately resulting in the suppression of STAT1 phosphorylation.
Boekhoudt
Gunther H
GH
U.S. Food and Drug Administration, Division of Monoclonal Antibodies, Office of Biotechnology Products, OPS, CDER, FDA, 29 Lincoln Drive, Bethesda, MD 20892, USA.
Frazier-Jessen
Michelle R
MR
Feldman
Gerald M
GM
D000936:Antigen-Antibody Complex / Q000494:pharmacology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007142:Immunoglobulin gamma-Chains; D007371:Interferon-gamma / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism*; D010766:Phosphorylation; D054645:Protein Phosphatase 1; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism; D017452:Receptors, IgG / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction
D000936:Antigen-Antibody Complex; C489017:FCGR1A protein, human; D007142:Immunoglobulin gamma-Chains; D017452:Receptors, IgG; D050794:STAT1 Transcription Factor; D007371:Interferon-gamma; D054645:Protein Phosphatase 1; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6