Cross Talk Between Interferon-γ and -α/β Signaling Components in Caveolar Membrane Domains
Abstract
Definition of cellular responses to cytokines often involves cross-communication through their respective receptors. Here, signaling by interferon-γ (IFN-γ) is shown to depend on the IFN-α/β receptor components. Although these IFNs transmit signals through distinct receptor complexes, the IFN-α/β receptor component, IFNAR1, facilitates efficient assembly of IFN-γ–activated transcription factors. This cross talk is contingent on a constitutive subthreshold IFN-α/β signaling and the association between the two nonligand-binding receptor components, IFNAR1 and IFNGR2, in the caveolar membrane domains. This aspect of signaling cross talk by IFNs may apply to other cytokines.
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The result of the antiviral assay presented in figure 2A of U. Müller et al. [Science 264, 1918 (1994)] is consistent with our present results. To investigate further the extent to which the loss of IFNAR1 affects IFN-γ–induced gene expression, we examined the mRNA induction kinetics for IRF-1 and 2′,5′OAS genes by IFN-γ in the WT and IFNAR1-null MEFs. The induction of IRF-1 mRNA by IFN-γ was six times lower in the mutant MEFs than in the WT MEFs. We also examined the induction of 2′,5′OAS mRNA, which is dependent on ISGF3, in the WT and IFNAR1-null MEFs. The induction of 2′,5′OAS mRNA by IFN-γ remained undetectable in IFNAR1-null MEFs throughout the time course tested (19).
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IFNAR1-deficient and IFNGR1-deficient mice were purchased from B&K Universal Group (North Humberside, UK). MEFs and splenocytes were prepared according to standard methods [
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Flow cytometry and immunoblot analyses revealed that the expression levels of IFNGR1 and IFNGR2 in these cells are essentially the same as in the WT MEFs. Immunoblot analysis showed that nearly the same amount of endogenous Stat1 protein was detected in the WT and IFNAR1-null MEFs.
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Detergent-free caveolae fractions were prepared as described [
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Preparation of whole-cell extracts, binding reactions, and gel electrophoresis were done as described [
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]. Unless otherwise noted, cells were treated with IFN-γ (250 U/ml) for 30 min. Equal amounts of proteins from whole-cell extracts were loaded onto each lane. Experiments were done in triplicate and were performed separately with at least two independent clones of MEFs derived from the same littermates of the WT or mutant mice.
34
After the treatment with IFN-γ (250 U/ml) for 15 min, cell lysis, immunoprecipitation, and immunoblotting were done as described [
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]. The following antibodies were purchased: anti-phosphotyrosine, anti-Jak1, and anti-Jak2 (Upstate Biotechnology); anti-Stat1 p84/p91 and anti-Stat2 (Santa Cruz); anti-phosphorylated Stat1 (Tyr701) (New England BioLabs); anti-IFNAR1, anti-IFNGR1, and anti-IFNGR2 (Research Diagnostics); and anti-caveolin (Transduction Laboratories).
35
We thank G. Uzé for the murine IFNAR1 cDNA (GenBank accession number ); J. Vilcek and E. L. Barsoumian for invaluable advice; M. Asagiri, N. Hata, Y. Kato, and S. H. Kim for technical support; Sumitomo Pharmaceuticals for purified murine IFN-α; and Toray Industries for recombinant murine IFN-β. Animal care was in accordance with institutional guidelines of the University of Tokyo. Supported by grants from the Research for the Future Program (96L00307), Yamanouchi Foundation for Research on Metabolic Disorders, the Japan Society for the Promotion of Science, Advanced Research on Cancer, and the Human Frontier Science Program Organization.
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Published In
Science
Volume 288 | Issue 5475
30 June 2000
30 June 2000
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Received: 9 February 2000
Accepted: 2 May 2000
Published in print: 30 June 2000
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