STAT4 and STAT6 regulate systemic inflammation and protect against lethal endotoxemia
Open accessAbstract
Members of the signal transducer and activator of transcription (STAT) family are transcription factors that mediate many of the effects of pro- and anti-inflammatory cytokines. The progressive systemic inflammatory response induced by endotoxin is mediated by overzealous cytokine production. Here we identify STAT4 and STAT6 as critical regulators of the systemic inflammatory response to endotoxin. Mice deficient for STAT4 or STAT6 were highly susceptible to lethal endotoxemia. In STAT4(-/-) mice, antibody blockade of IL-12 prevented mortality, suggesting that STAT4 confers protection, while another signaling pathway mediates the detrimental effects of IL-12. In STAT6(-/-) mice we observed dysregulated activation of the transcription factor NF-kappaB, resulting in augmented production of proinflammatory cytokines and chemokines. Furthermore, STAT6(-/-) mice displayed increased organ accumulation of leukocytes and significant hepatocellular injury. These findings demonstrate that STAT4 and STAT6 confer protection against endotoxin-induced death and that for STAT6 these protective effects occur through the regulation of NF-kappaB activation and subsequent production of proinflammatory cytokines and chemokines.
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STAT6 downregulates Il6 expression.
“STAT6, which downregulates Il6 expression 58”
From Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis (2024) · cites this paper as [58]
Table 1 (p. 1478) shows higher IL-6 levels in the liver and lung of STAT6-deficient mice than in wild-type mice 24 hours after endotoxin administration. The ‘Augmented cytokine and chemokine expression’ section describes this as increased IL-6 protein expression. That supports a role for STAT6 in limiting IL-6 under this condition, but not an unqualified claim that STAT6 downregulates Il6 expression generally. (LLM, conf=0.84)
Experimental — accuracy not yet measuredSTAT6 is known to downregulate Il6 expression.
“known to downregulate Il6 expression 58”
From Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis (2024) · cites this paper as [58]
Enhanced activity of STAT6 was seen in hepatic stellate cells from NASH mice lacking Treg cell-derived Areg compared to controls.
“enhanced activity of STAT6 - known to downregulate Il6 expression 58 - was seen in hepatic stellate cells from NASH mice lacking Treg cell-derived Areg compared to controls (Fig. 4G).”
From Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis (2024) · cites this paper as [58]
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- Authors
- Lentsch, A. B., Kato, A., Davis, B., Wang, W., Chao, C., & Edwards, M. J.
- Affiliations
- University of Louisville (US)
- Corresponding author
- Lentsch, Alex B.
- Venue
- Journal of Clinical Investigation
- Published
- 2001-11-15
- Volume
- 108
- Issue
- 10
- Pages
- 1475-1482
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC209422
- OpenAlex
- W4250194912
- Cited by
- 63
- References
- 31
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 6 · 2023: 5 · 2022: 5 · 2021: 3 · 2020: 2 · 2018: 2 · 2017: 1 · 2016: 2 · 2015: 4 · 2012: 1
- FWCI
- 1.63
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 56029, R01DK056029)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- STAT4, STAT6, endotoxemia, systemic inflammation, IL-12, NF-κB, inflammatory cytokines, chemokines, hepatocyte injury, leukocyte accumulation, cytokine signaling, transcription factors
- MeSH terms
- Animals, DNA-Binding Proteins, Inflammation, Mice, Inbred BALB C, Trans-Activators, NF-kappa B, Endotoxemia, STAT4 Transcription Factor, STAT6 Transcription Factor, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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