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Cited by 225Cytokine Signaling Pathways and InteractionsImmunotherapy and Immune ResponsesT-cell and B-cell Immunology

Dendritic cell (DC)-specific targeting reveals Stat3 as a negative regulator of DC function

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Melillo, Jessica A, Song, Li, Bhagat, Govind, Blazquez, Ana Belen, Plumlee, Courtney R, Lee, Carolyn, Berin, Cecilia, Reizis, Boris +1 more·2010·The Journal of Immunology
DOI 10.4049/jimmunol.0902960PMC PMC3099405
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Abstract

Dendritic cells (DCs) must achieve a critical balance between activation and tolerance, a process influenced by cytokines and growth factors. IL-10, which transduces signals through Stat3, has emerged as one important negative regulator of DC activation. To directly examine the role Stat3 plays in regulating DC activity, the Stat3 gene was targeted for deletion with a CD11c-cre transgene. Stat3 CKO mice developed cervical lymphadenopathy as well as a mild ileocolitis that persisted throughout life and was associated with impaired weight gain. Consistent with this, Stat3-deficient DCs demonstrated enhanced immune activity, including increased cytokine production, Ag-dependent T-cell activation and resistance to IL-10–mediated suppression. These results reveal a cell-intrinsic negative regulatory role of Stat3 in DCs and link increased DC activation with perturbed immune homeostasis and chronic mucosal inflammation.

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  • STAT3 suppresses TLR signaling in mature phagocytes by suppressing NF-κB and MAPK through direct transcriptional repression of an E2 ubiquitin-conjugating enzyme required for TLR signaling.

    “STAT3 suppresses TLR signaling in mature phagocytes”

    From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Melillo et al., 2010

    The Discussion reports increased TLR-dependent IL-12 and IL-23 secretion in Stat3-deficient dendritic cells, supporting a negative regulatory role for STAT3 in those cells. It does not establish the claim across mature phagocytes generally, or the proposed mechanism involving NF-κB, MAPK, and direct repression of an E2 ubiquitin-conjugating enzyme. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • STAT3-deficient macrophages, neutrophils, and dendritic cells and hematopoietic-specific STAT3-KO mice have increased production of inflammatory cytokines.

    “STAT3-deficient macrophages, neutrophils, and DCs”

    From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Melillo et al., 2010

    The Results (Functional characterization of Stat3 CKO DCs; page unavailable) report significantly increased IL-12 and IL-23 secretion by stimulated Stat3-deficient dendritic cells. The Discussion describes macrophage-predominant IL-12 secretion in a myeloid-specific deletion model, but does not establish increased cytokine production by STAT3-deficient neutrophils. It describes inflammation after broader hematopoietic deletion without establishing the claimed cytokine increase for those mice. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

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Authors
Melillo, J. A., Song, L., Bhagat, G., Blazquez, A. B., Plumlee, C. R., Lee, C., Berin, C., Reizis, B., & Schindler, C.
Affiliations
  • Department of Biological Sciences , New York, NY 10032
  • Department of Microbiology and Immunology , New York, NY 10032
  • Department of Pathology , New York, NY 10032
  • Department of Pediatrics, Mount Sinai School of Medicine , New York, NY 10029
  • Columbia University (US)
Corresponding author
  • Reizis, Boris
  • Schindler, Christian
ORCID
Venue
The Journal of Immunology
Publisher
Oxford University Press (OUP)
Published
2010-03-01
Volume
184
Issue
5
Pages
2638-2645
ISSN
  • 0022-1767 (ISSN-L)
  • 1550-6606
DOI
10.4049/jimmunol.0902960
PMC
PMC3099405
OpenAlex
W1919712230
Cited by
225
References
4
Citations by year
2026: 11 · 2025: 6 · 2024: 10 · 2023: 8 · 2022: 20 · 2021: 16 · 2020: 18 · 2019: 14 · 2018: 16 · 2017: 15 · 2016: 8 · 2015: 10 · 2014: 19 · 2013: 22 · 2012: 22
FWCI
8.55
Type
journal article
Language
en
Open access
Licence
academic.oup.com/pages/standard-publication-reuse-rights (vor, 5504 d)
Locations
  • The Journal of Immunology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (AI 058211, HL 55413, AI067804, 5T32 AI07525, AI044236)
  • Burroughs Wellcome Fund (APP#2010)
Topics
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords
dendritic cells, STAT3, IL-10 signaling, lymphadenopathy, ileocolitis, immune homeostasis, mucosal inflammation, T cell activation, cytokine production
MeSH terms
Animals, Cells, Cultured, Crohn Disease, Dendritic Cells, Enzyme-Linked Immunosorbent Assay, Female, Flow Cytometry, Interferon-gamma, Lymphatic Diseases, Male, Mice, Inbred C57BL, Mice, Inbred Strains, Mice, Transgenic, Tumor Necrosis Factor-alpha, Cytokines, Interleukin-10, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, CD11c Antigen, STAT3 Transcription Factor, Mice

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