FcgammaRIII-dependent inhibition of interferon-gamma responses mediates suppressive effects of intravenous immune globulin.
Intravenous immune globulin (IVIG) suppresses autoantibody-mediated inflammation by inducing and activating the inhibitory Fc receptor FcgammaRIIb and downstream negative signaling pathways. We investigated the effects of IVIG on cellular responses to interferon-gamma (IFN-gamma), a potent macrophage activator that exacerbates inflammation. Our study showed that IVIG blocked IFN-gamma signaling and IFN-gamma-induced gene expression and suppressed IFN-gamma function in vivo during immune responses to Listeria monocytogenes and in an IFN-gamma-enhanced model of immune thrombocytopenic purpura. The mechanism of inhibition of IFN-gamma signaling was suppression of expression of the IFNGR2 subunit of the IFN-gamma receptor. The inhibitory effect of IVIG was mediated at least in part by soluble immune complexes and was dependent on FcgammaRIII but independent of FcgammaRIIb. These results reveal an unexpected inhibitory role for the activating FcgammaRIII in mediating suppression of IFN-gamma signaling and suggest that inhibition of macrophage responses to IFN-gamma contributes to the anti-inflammatory properties of IVIG.
Park-Min
Kyung-Hyun
KH
Graduate Program in Immunology and Microbial Pathogenesis, Weill Medical College and Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10021, USA.
Serbina
Natalya V
NV
Yang
Wentian
W
Ma
Xiaojing
X
Krystal
Gerald
G
Neel
Benjamin G
BG
Nutt
Stephen L
SL
Hu
Xiaoyu
X
Ivashkiv
Lionel B
LB
D000818:Animals; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D015151:Immunoblotting; D016756:Immunoglobulins, Intravenous / Q000276:immunology / Q000494:pharmacology*; D007371:Interferon-gamma / Q000187:drug effects* / Q000276:immunology; D008088:Listeriosis / Q000276:immunology; D008262:Macrophage Activation / Q000187:drug effects* / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000188:drug therapy; D017452:Receptors, IgG / Q000276:immunology* / Q000627:therapeutic use; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D014162:Transfection
D016756:Immunoglobulins, Intravenous; D017452:Receptors, IgG; D007371:Interferon-gamma