Toll-like receptor-dependent production of IL-12p40 causes chronic enterocolitis in myeloid cell-specific Stat3-deficient mice
Masaya Kobayashi, … , Kiyoshi Takeda, Shizuo Akira
Masaya Kobayashi, … , Kiyoshi Takeda, Shizuo Akira
Published May 1, 2003
Citation Information: J Clin Invest. 2003;111(9):1297-1308. https://doi.org/10.1172/JCI17085.
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Article Immunology

Toll-like receptor-dependent production of IL-12p40 causes chronic enterocolitis in myeloid cell-specific Stat3-deficient mice

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-γ signaling pathways, Stat3 mutant mice developed chronic enterocolitis. TNF-α/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-γ 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.

Authors

Masaya Kobayashi, Mi-Na Kweon, Hirotaka Kuwata, Robert D. Schreiber, Hiroshi Kiyono, Kiyoshi Takeda, Shizuo Akira

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Macrophages and dendritic cells in the large intestine were increased in...
Macrophages and dendritic cells in the large intestine were increased in number and produced IL-12p40 in Stat3 mutant mice with colitis. (a–f) Immunohistochemistry of the colon of (a, c, e) control and (b, d, f) Stat3 mutant mice at 16 weeks. The colon sections were stained with anti-CD11c Ab (green) (a, b, e, f), anti-CD11b Ab (red) (c and d), and anti-CD3 Ab (red) (e and f). Bar: 10 μm. (g) CD11c-positive dendritic cells in the large intestine were stimulated with 100 ng/ml LPS for 24 h. Concentrations of IL-6 and IL-12p40 in the culture supernatants were measured. *Not detected. (h) Immunohistochemistry of the colon of Stat3 mutant mice. The colon sections were stained with anti–IL-12p40 Ab (red) and anti-CD11c Ab (green) oranti-CD11b Ab (green). Bar: 10 μm.