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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Improved colitis in TLR4/Stat3 double-mutant mice. (a) Peritoneal macrop...
Improved colitis in TLR4/Stat3 double-mutant mice. (a) Peritoneal macrophages were stimulated with 10 ng/ml LPS for 24 h. Concentrations of TNF-α, IL-6, and IL-12p40 in the culture supernatants were measured. LPS-induced production of inflammatory cytokines was abolished in TLR4/Stat3 double-mutant macrophages. *Not detected. (b) CD4+ T cells were purified from spleen and stimulated with plate-bound anti-CD3 Ab. The concentration of IFN-γ was measured by ELISA. CD4+ T cells from TLR4/Stat3 double-mutant mice produced reduced levels of IFN-γ compared with Stat3 mutant mice. (c–e) Histopathology of the colon of (c) control, (d) TLR4-deficient, and (e) TLR4/Stat3 double-mutant mice at 16 weeks. H&E staining is shown. ×20. (f) The colitis score of TLR4/Stat3 double-mutant mice at 16 weeks of age. TLR4/Stat3 double-mutant mice showed no or moderate inflammatory changes in the colon. *P < 0.001 between Stat3 mutant mice and control or TLR4/Stat3 double-mutant mice.