Abstract
Stat3 plays an essential role in IL-10 signaling pathways. A myeloid cell-specific deletion of Stat3 resulted in inflammatory cytokine production and development of chronic enterocolitis with enhanced Th1 responses in mice. In this study, we analyzed the mechanism by which a Stat3 deficiency in myeloid cells led to the induction of chronic enterocolitis in vivo. Even in the absence of Stat1, which is essential for IFN-gamma signaling pathways, Stat3 mutant mice developed chronic enterocolitis. TNF-alpha/Stat3 double-mutant mice developed severe chronic enterocolitis with enhanced Th1 cell development. IL-12p40/Stat3 double-mutant mice, however, showed normal Th1 responses and no inflammatory change in the colon. RAG2/Stat3 double-mutant mice did not develop enterocolitis, either. These findings indicate that overproduction of IL-12p40, which induces potent Th1 responses, is essential for the development of chronic enterocolitis in Stat3 mutant mice. Furthermore, enterocolitis was significantly improved and IFN-gamma production by T cells was reduced in TLR4/Stat3 double-mutant mice, indicating that TLR4-mediated recognition of microbial components triggers aberrant IL-12p40 production by myeloid cells, leading to the development of enterocolitis. Thus, this study clearly established a sequential innate and acquired immune mechanism for the development of Th1-dependent enterocolitis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Chronic Disease
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Dendritic Cells / immunology
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Dendritic Cells / metabolism
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Drosophila Proteins*
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Enterocolitis / metabolism*
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Enterocolitis / pathology
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Interferon-gamma / metabolism
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Interleukin-10 / metabolism
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Interleukin-12 / genetics
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Interleukin-12 / metabolism*
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Interleukin-12 Subunit p40
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Lipopolysaccharides / pharmacology
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Macrophages / drug effects
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Macrophages / metabolism
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Membrane Glycoproteins / metabolism*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Myeloid Cells / cytology
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Myeloid Cells / physiology*
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Protein Subunits / genetics
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Protein Subunits / metabolism*
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Proteins / metabolism
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Receptors, Cell Surface / metabolism*
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Repressor Proteins*
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STAT1 Transcription Factor
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STAT3 Transcription Factor
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Spleen / cytology
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism
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Toll-Like Receptor 4
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Toll-Like Receptors
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Trans-Activators / genetics
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Trans-Activators / metabolism*
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Transcription Factors*
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / metabolism
Substances
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DNA-Binding Proteins
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Drosophila Proteins
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Interleukin-12 Subunit p40
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Lipopolysaccharides
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Membrane Glycoproteins
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Protein Subunits
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Proteins
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Rag2 protein, mouse
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Receptors, Cell Surface
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Repressor Proteins
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SOCS3 protein, human
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STAT1 Transcription Factor
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STAT3 Transcription Factor
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Socs3 protein, mouse
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Stat1 protein, mouse
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Stat3 protein, mouse
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins
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Toll-Like Receptor 4
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Toll-Like Receptors
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Trans-Activators
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Transcription Factors
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Tumor Necrosis Factor-alpha
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V(D)J recombination activating protein 2
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Interleukin-10
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Interleukin-12
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Interferon-gamma