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Cited by 69Sepsis Diagnosis and TreatmentNF-κB Signaling PathwaysCytokine Signaling Pathways and Interactions

JAK2 inhibition prevents innate immune responses and rescues animals from sepsis

Open access
Peña, Geber, Cai, Bolin, Deitch, Edwin A., Ulloa, Luis·2010·Journal of Molecular Medicine
DOI 10.1007/s00109-010-0628-zPMC PMC3083634
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Abstract

Sepsis, a leading cause of death in hospitalized patients, is characterized by lethal systemic inflammatory responses. JAK2 is an essential tyrosine kinase modulating immune responses. However, the implications of JAK2 in infectious disorders remain undetermined. Here, we report that JAK2 inhibitors rescue animals from polymicrobial sepsis in a clinically relevant time frame. JAK2 inhibition with AG490 prevents NF-kappaB activation, modulates macrophage activation, and restrains the production of inflammatory cytokines. The inhibition of JAK2 blunted TNF production in both macrophages and splenocytes in a concentration-dependent manner. JAK2 inhibition specifically prevents LPS-induced STAT3 tyrosine phosphorylation without affecting serine phosphorylation in macrophages. JAK2 inhibitor prevents the activation of the canonical p65RelA/p50NF-kappaB1 pathway but not the other NF-kappaB proteins. In vivo, JAK2 inhibition restrains serum TNF levels by modulating TNF production in the lung and the spleen and protects mice from lethal endotoxemia in a concentration-dependent manner. AG490 also inhibits extracellular release of HMGB1 from macrophages and prevents an increase in serum HMGB1 levels during sepsis. JAK2 inhibition started at 24 h after the onset of sepsis rescued the mice from polymicrobial sepsis. Our study is the first experimental evidence that JAK2 inhibitors may provide a pharmacological advantage for the treatment of sepsis in a clinically relevant time frame.

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  • AG490 treatment protected against liver and lung injury and improved survival in CLP-induced sepsis and LPS-induced toxic shock in mice.

    “AG490 treatment protected against liver and lung injury and improved survival in CLP‐induced sepsis and LPS‐induced toxic shock in mice. 29 , 30 , 31”

    From Sepsis induces interleukin 6, gp130/JAK2/STAT3, and muscle wasting (2022) · cites this paper as [29]

    The Results report improved survival after AG490 treatment in mice with CLP-induced sepsis and in LPS-induced endotoxemia. They report reduced TNF in the lung, but not the liver; reduced TNF is not itself evidence of protection against lung injury. The Discussion says the authors did not observe organ dysfunction or liver injury, so this paper does not establish that AG490 protected against liver and lung injury. (LLM, conf=0.88)

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  • AG490 leads to a reduction in TNF plasma levels in septic mice.

    “Peña et al. showed that AG490 leads to a reduction in TNF plasma levels in septic mice. 29”

    From Sepsis induces interleukin 6, gp130/JAK2/STAT3, and muscle wasting (2022) · cites this paper as [29]

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Research works printed but not linked: 30

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Authors
Peña, G., Cai, B., Deitch, E. A., & Ulloa, L.
Affiliations
  • Rutgers, The State University of New Jersey (US)
  • Rutgers New Jersey Medical School (US)
Corresponding author
Ulloa, Luis
ORCID
Ulloa, Luis
Venue
Journal of Molecular Medicine
Publisher
Springer Science and Business Media LLC
Published
2010-04-15
Volume
88
Issue
8
Pages
851-859
ISSN
  • 0946-2716 (ISSN-L)
  • 1432-1440
DOI
10.1007/s00109-010-0628-z
PMC
PMC3083634
OpenAlex
W2135306743
Cited by
69
References
4
Citations by year
2026: 2 · 2025: 2 · 2024: 2 · 2023: 3 · 2022: 3 · 2021: 6 · 2020: 7 · 2019: 4 · 2018: 8 · 2017: 9 · 2016: 3 · 2015: 5 · 2014: 3 · 2013: 5 · 2012: 2
FWCI
2.80
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Journal of Molecular Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute of General Medical Sciences (R01GM084125)
Topics
  • Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
Keywords
JAK2 inhibition, sepsis, polymicrobial sepsis, AG490, NF-κB activation, macrophage activation, TNF production, STAT3 tyrosine phosphorylation, HMGB1 release, endotoxemia, innate immune response, systemic inflammation
MeSH terms
Animals, Cell Line, Enzyme Inhibitors, Humans, Immunity, Innate, Macrophages, Male, Mice, Inbred C57BL, Tumor Necrosis Factor-alpha, Cytokines, NF-kappa B, Sepsis, Tyrphostins, HMGB1 Protein, STAT3 Transcription Factor, Mice, Janus Kinase 2

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