Abstract
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.
Highlights
IntroductionSubsequent analyses demonstrated that a functional receptor complex could be generated by expression of hu-IFN-␥R1 in hamster-human somatic cell hybrids that harbored human Chromosome 21 [14], suggesting that hu-IFN-␥-mediated signal transduction requires speciesspecific accessory protein(s) encoded by Chromosome 21
Studies on the composition of the human IFN-␥ receptor complex suggested that the hu-IFN-␥R2 chain encoded by human Chromosome 21 interacts with the extracellular domain of the hu-IFN-␥R1 chain in a species-specific manner (20, 21, 36 –38)
Class I antigens (14, 15, 17, 19 –21, 36, 37). These receptor complexes were unable to transduce the IFN-␥ signal to protect the cells from the cytopathic effects of vesicular stomatitis virus (VSV), and provided only partial resistance to encephalomyocarditis virus (EMCV) [15, 19, 21]
Summary
Subsequent analyses demonstrated that a functional receptor complex could be generated by expression of hu-IFN-␥R1 in hamster-human somatic cell hybrids that harbored human Chromosome 21 [14], suggesting that hu-IFN-␥-mediated signal transduction requires speciesspecific accessory protein(s) encoded by Chromosome 21. This hypothesis was later confirmed by the cloning of the human and mouse IFN-␥R2 chains (accessory factor-1, AF-1; designated IFN-␥R chain) [15, 16]. Others reported that hu-IFN-␥ induces the expression of MHC antigens, 2Ј,5Ј-oligoadenylate synthetase and protection or partial protection from EMCV and VSV cytopathic effect in a mouse-human somatic cell hybrid that harbored human Chromosome 21 and expressed a transfected hu-IFN␥R1 chain [20, 21].
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