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Cited by 132Cytokine Signaling Pathways and InteractionsProtein Tyrosine PhosphatasesNF-κB Signaling Pathways

Inhibition of cytokines and JAK-STAT activation by distinct signaling pathways.

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Sengupta, T K, Schmitt, E M, Ivashkiv, L B·1996·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.93.18.9499PMC PMC38457
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Abstract

An important component of cytokine regulation of cell growth and differentiation is rapid transcriptional activation of genes by the JAK-STAT (signal transducer and activator of transcription) signaling pathway. Ligation of cytokine receptors results in tyrosine phosphorylation and activation of receptor-associated Jak protein tyrosine kinases and cytoplasmic STAT transcription factors, which then translocate to the nucleus. We describe the interruption of cytokine triggered JAK-STAT signals by cAMP, the calcium ionophore ionomycin, and granulocyte/macrophage colony-stimulating factor. Jak1 kinase activity, interleukin 6-induced gene activation, Stat3 tyrosine phosphorylation, and DNA-binding were inhibited, as was activation of Jak1 and Stat1 by interferon gamma. The kinetics and requirement for new RNA and protein synthesis for inhibition of interleukin 6 by ionomycin and GM-CSF differed, but both agents increased the association of Jak1 with protein tyrosine phosphatase ID (SH2-containing phosphatase 2). Our results demonstrate that crosstalk with distinct signaling pathways can inhibit JAK-STAT signal transduction, and suggest approaches for modulating cytokine activity during immune responses and inflammatory processes.

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  • cAMP inhibits IL-6-induced DNA binding of STAT1 and STAT3.

    “cAMP has been found to inhibit IL-6–induced DNA binding of STAT1 and STAT3.116”

    From Cytokines and Glucocorticoid Receptor Signaling (2009) · cites this paper as [116]

    The Abstract reports inhibition of IL-6-induced STAT3 DNA binding in the context of cAMP-mediated interruption of JAK–STAT signaling. It describes STAT1 inhibition in response to interferon gamma, not IL-6, so the STAT1 portion of the claim is not supported. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • cAMP and PKA signaling pathways interact with cytokine signaling pathways, including NF-κB, MAPK and Jak-STAT pathways.

    “cAMP and PKA signaling pathways also interact with cytokine signaling pathways, including NF-κB, MAPK and Jak-STAT pathways.114–116”

    From Cytokines and Glucocorticoid Receptor Signaling (2009) · cites this paper as [116]

    The Abstract (page not specified in our copy) reports that cAMP interrupts cytokine-triggered JAK–STAT signaling. It does not establish interactions with NF-κB or MAPK; PKA appears in a cited reference concerning JAK–STAT, rather than in the paper’s reported findings. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Sengupta, T. K., Schmitt, E. M., & Ivashkiv, L. B.
Affiliations
Hospital for Special Surgery (US)
Corresponding author
Ivashkiv, L B
ORCID
Ivashkiv, L B
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
1996-09-03
Volume
93
Issue
18
Pages
9499-9504
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.93.18.9499
PMC
PMC38457
OpenAlex
W1983453744
Cited by
132
References
0
Citations by year
2026: 3 · 2025: 4 · 2023: 1 · 2021: 7 · 2020: 1 · 2019: 1 · 2018: 3 · 2017: 4 · 2016: 4 · 2015: 5 · 2014: 1 · 2013: 1
FWCI
5.53
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Arthritis Foundation
  • National Institutes of Health
Topics
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
Keywords
JAK/STAT signaling, cytokine signaling, signal transduction inhibition, cyclic AMP, ionomycin, calcium ionophore, GM-CSF, JAK1, STAT3 tyrosine phosphorylation, STAT1, interferon-gamma, interleukin-6, protein tyrosine phosphatase, signaling crosstalk, transcriptional activation
MeSH terms
Interleukin-6 Inhibitors, Cyclic AMP, Cells, Cultured, Cycloheximide, Dactinomycin, DNA, DNA-Binding Proteins, Enzyme Activation, Humans, Interferon-gamma, Protein-Tyrosine Kinases, RNA, Transcription, Genetic, Blotting, Northern, Signal Transduction, Trans-Activators, Ionomycin, Granulocyte-Macrophage Colony-Stimulating Factor, Cytokines, Protein Tyrosine Phosphatases, Intracellular Signaling Peptides and Proteins, STAT1 Transcription Factor, STAT3 Transcription Factor, Janus Kinase 1, Janus Kinase 3, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Protein Phosphatase 2

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