Analysis on regulation of macrophage activity by cytokines and endotoxin

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Stat3 plays an essential role in IL-10 signaling pathways. A myeloid cell-specific deletion of Slat3 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 Slat3 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, Slat3 mutant mice developed chronic enterocolitis. TNF-α/Stat3 double mutant mice developed severe chronic enterocolitis with enhanced Th1 cell development. However, IL-12p40/Stat3 double mutant mice 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 ILR4/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.