Cells Previously Desensitized to Type 1 Interferons Display Different Mechanisms of Activation of Stat-dependent Gene Expression from Naïve Cells
Open accessAbstract
Over the past decade, a wealth of knowledge has been obtained concerning the mechanisms by which interferons (IFNs) and other cytokines activate or down-regulate immediate early genes via the Jak/Stat pathway. In contrast, little information is available on interferon-activated gene expression in naïve cells compared with cells that have been desensitized and subsequently resensitized to the actions of these cytokines. In naïve cells, the ISG54 gene is activated via IFN beta-stimulated formation of ISGF3, a heterotrimeric DNA binding complex consisting of p48 (IRF9) and tyrosine-phosphorylated Stat1 and Stat2. In contrast, in previously desensitized cells IFN beta weakly stimulates the assembly of an ISGF3-like complex that lacks Stat1, even though ISG54 mRNA induction is the same as in naïve cells. The lack of Stat1 tyrosine phosphorylation and DNA binding is due to increased activity of a protein-tyrosine phosphatase. In cells that do not express the tyrosine phosphatase Tc-PTP, the rate of Stat1 dephosphorylation is the same in naïve and previously desensitized cells. These results implicate Tc-PTP in a novel role in the regulation of type 1 interferon-stimulated gene expression.
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T-cell protein-tyrosine phosphatase has been shown to potently desensitize cells to repeated IFNγ stimulation.
“In the case of IFN␥ signaling, the T-cell protein-tyrosine phosphatase has been shown to potently desensitize cells to repeated stimulation (28).”
From The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling (2006) · cites this paper as [28]
The Results passages describing Figs. 5–6 show reduced IFNγ-induced Stat1 activation after IFNβ pretreatment and implicate Tc-PTP in enhanced Stat1 dephosphorylation. They do not show desensitization caused by repeated IFNγ stimulation; the prior exposure was to IFNβ. Page numbers are not available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredFactors other than SOCS1, such as T-cell protein-tyrosine phosphatase, also have an important role in desensitizing cells to IFNγ.
“This result also highlighted the important role that factors other than SOCS1, such as T-cell protein-tyrosine phosphatase for instance (28), also have in desensitizing cells to IFN␥.”
From The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling (2006) · cites this paper as [28]
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Complex modulation of cell type-specific signaling in response to type I interferons
van Boxel-Dezaire, A. H. H., Rani, M. R. S., & Stark, G. R. (2006) · Immunity · doi:10.1016/j.immuni.2006.08.014 · Cited by 530 · see citing works
Wormald, S., Zhang, J.-G., Krebs, D. L., Mielke, L. A., Silver, J., Alexander, W. S., Speed, T. P., Nicola, N. A., & Hilton, D. J. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m509595200 · Cited by 123 · see citing works
- Authors
- Sakamoto, S., Qin, J., Navarro, A., Gamero, A., Potla, R., Yi, T., Zhu, W., Baker, D. P., Feldman, G., & Larner, A. C.
- Affiliations
- Cleveland Clinic (US)
- Cleveland Clinic Research (US)
- Biogen (United States) (US)
- Center for Biologics Evaluation and Research (US)
- Corresponding author
- Larner, Andrew C.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2004-01
- Volume
- 279
- Issue
- 5
- Pages
- 3245-3253
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2033067962
- Cited by
- 31
- References
- 3
- Citations by year
- 2026: 2 · 2025: 2 · 2022: 1 · 2019: 1 · 2018: 1 · 2015: 1 · 2014: 2 · 2013: 1 · 2012: 2
- FWCI
- 1.20
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ca077366-05)
- National Cancer Institute (CA77366)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- type I interferon, interferon-beta, STAT1, STAT2, IRF9, ISGF3, ISG54, JAK/STAT signaling, protein tyrosine phosphatase, TCPTP, interferon-stimulated gene expression
- MeSH terms
- Animals, Cell Line, Cell Nucleus, Cells, Cultured, Chromatin, Cytoplasm, DNA-Binding Proteins, Gene Expression Regulation, Humans, Immunoglobulins, Interferon Type I, Membrane Proteins, Phosphorylation, Precipitin Tests, Protein Binding, RNA, RNA, Messenger, Time Factors, Tyrosine, Blotting, Western, Trans-Activators, Down-Regulation, Interferon-beta, Protein Tyrosine Phosphatases, STAT1 Transcription Factor, Mice, Protein Tyrosine Phosphatase, Non-Receptor Type 1, Protein Tyrosine Phosphatase, Non-Receptor Type 2
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