Mouse macrophages carrying both subunits of the human interferon-gamma (IFN-gamma) receptor respond to human IFN-gamma but do not acquire full protection against viral cytopathic effect.
Studies of hamster-human and mouse-human somatic fibroblast hybrids and transfected mouse fibroblasts have demonstrated that signaling through the human interferon-gamma receptor (hu-IFN-gammaR) requires the formation of a complex consisting of ligand (IFN-gamma), a ligand binding receptor chain (IFN-gammaR1), and a signal transducing receptor chain (IFN-gammaR2). To date, the ability of this receptor complex to transduce the full repertoire of biological signals has been difficult to assess due to the limited number of activities that IFN-gamma can exert on fibroblasts. The current report assesses the ability of hu-IFN-gammaR chains to transduce signals in the absence of background human gene products by expressing hu-IFN-gammaR2 in a transformed macrophage cell line (F10/96) derived from a hu-IFN-gammaR1 transgenic mouse. Our results indicate that F10/96 clones expressing both human receptor proteins bind hu-IFN-gamma with an affinity comparable to that of human cells. Binding of either human or mouse IFN-gamma to its respective receptor elicits classic IFN-gamma responses such as up-regulation of major histocompatibility complex antigens, enhanced expression of IRF-1, and increased production of NO2- radicals, interleukin-6, tumor necrosis factor-alpha, and granulocyte macrophage-colony stimulating factor. However, hu-IFN-gamma could not fully protect the clones from cytopathic effects of encephalomyocarditis virus and vesicular stomatitis virus while mo-IFN-gamma could. These results demonstrate that while co-expression of hu-IFN-gammaR1 and hu-IFN-gammaR2 is necessary and sufficient for most IFN-gamma-induced responses, it is not sufficient to confer a generalized antiviral state. These findings further suggest that additional species-specific accessory factor(s) are necessary for full signaling potential through the IFN-gamma receptor complex. The nature and potential role of such factors in IFN-gammaR signaling is discussed.
Lembo
D
D
Hoffmann-La Roche Ltd., 4070 Basel, Switzerland.
Ricciardi-Castagnoli
P
P
Alber
G
G
Ozmen
L
L
Landolfo
S
S
Blüthmann
H
H
Dembic
Z
Z
Kotenko
S V
SV
Cook
J R
JR
Pestka
S
S
Garotta
G
G
D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D001854:Bone Marrow Cells; D003588:Cytopathogenic Effect, Viral; D004268:DNA-Binding Proteins / Q000502:physiology; D015870:Gene Expression; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D050856:Interferon Regulatory Factor-1; D007371:Interferon-gamma / Q000502:physiology*; D015850:Interleukin-6 / Q000378:metabolism; D008024:Ligands; D046911:Macromolecular Substances; D008262:Macrophage Activation; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000378:metabolism; D010750:Phosphoproteins / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics; D017471:Receptors, Interferon / Q000502:physiology*; D015398:Signal Transduction; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000096743:Interferon gamma Receptor
D015703:Antigens, CD; D004268:DNA-Binding Proteins; D016179:Granulocyte Colony-Stimulating Factor; D050856:Interferon Regulatory Factor-1; D007371:Interferon-gamma; D015850:Interleukin-6; D008024:Ligands; D046911:Macromolecular Substances; D009569:Nitric Oxide; D010750:Phosphoproteins; D012333:RNA, Messenger; D017471:Receptors, Interferon; D014409:Tumor Necrosis Factor-alpha; D000096743:Interferon gamma Receptor; C494257:IRF1 protein, human; C494258:Irf1 protein, mouse