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Cited by 381Cytokine Signaling Pathways and InteractionsInflammatory Bowel DiseasePsoriasis: Treatment and Pathogenesis

STAT3 deletion during hematopoiesis causes Crohn’s disease-like pathogenesis and lethality: a critical role of STAT3 in innate immunity

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Welte, Thomas, Zhang, Samuel S. M., Wang, Tian, Zhang, Zhiyuan, Hesslein, David G. T., Yin, Zhinan, Kano, Arihiro, Iwamoto, Yoshiki +7 more·2003·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0237137100PMC PMC149927
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Abstract

Signal transducer and activator of transcription 3 (STAT3) is a key transcriptional mediator for many cytokines and is essential for normal embryonic development. We have generated a unique strain of mice with tissue-specific disruption of STAT3 in bone marrow cells during hematopoiesis. This specific STAT3 deletion causes death of these mice within 4-6 weeks after birth with Crohn's disease-like pathogenesis in both the small and large intestine, including segmental inflammatory cell infiltration, ulceration, bowel wall thickening, and granuloma formation. Deletion of STAT3 causes significantly increased cell autonomous proliferation of cells of the myeloid lineage, both in vivo and in vitro. Most importantly, Stat3 deletion during hematopoiesis causes overly pseudoactivated innate immune responses. Although inflammatory cytokines, including tumor necrosis factor alpha and IFN-gamma, are overly produced in these mice, the NAPDH oxidase activity, which is involved in antimicrobial and innate immune responses, is inhibited. The signaling responses to lipopolysaccharide are changed in the absence of STAT3, leading to enhanced NF-kappa B activation. Our results suggest a model in which STAT3 has critical roles in the development and regulation of innate immunity, and deletion of STAT3 during hematopoiesis results in abnormalities in myeloid cells and causes Crohn's disease-like pathogenesis.

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Authors
Welte, T., Zhang, S. S. M., Wang, T., Zhang, Z., Hesslein, D. G. T., Yin, Z., Kano, A., Iwamoto, Y., Li, E., Craft, J. E., Bothwell, A. L. M., Fikrig, E., Koni, P. A., Flavell, R. A., & Fu, X.-Y.
Affiliations
Howard Hughes Medical Institute (US)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2003-02-05
Volume
100
Issue
4
Pages
1879-1884
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0237137100
PMC
PMC149927
OpenAlex
W2148996267
Cited by
381
References
44
Citations by year
2026: 1 · 2025: 8 · 2024: 3 · 2023: 6 · 2022: 4 · 2021: 12 · 2020: 14 · 2019: 16 · 2018: 8 · 2017: 14 · 2016: 19 · 2015: 15 · 2014: 25 · 2013: 24 · 2012: 19
FWCI
12.86
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Howard Hughes Medical Institute
  • Österreichischen Akademie der Wissenschaften
  • National Institutes of Health (5r01ar044906-05)
  • National Institute of Allergy and Infectious Diseases (AI-34522, R01AI034522)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR44906)
Topics
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
  • Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
Keywords
STAT3, Crohn's disease, hematopoiesis, bone marrow, innate immunity, myeloid cell proliferation, intestinal inflammation, NF-κB activation, lipopolysaccharide signaling, TNF-α, interferon-gamma, granuloma formation, tissue-specific gene deletion
MeSH terms
Animals, Bone Marrow Cells, Cells, Cultured, Crohn Disease, DNA-Binding Proteins, Hematopoiesis, Immunity, Trans-Activators, Gene Deletion, STAT3 Transcription Factor, Mice

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