Enhanced Th1 Activity and Development of Chronic Enterocolitis in Mice Devoid of Stat3 in Macrophages and Neutrophils

Abstract

We have generated mice with a cell type-specific disruption of the Stat3 gene in macrophages and neutrophils. The mutant mice are highly susceptible to endotoxin shock with increased production of inflammatory cytokines such as TNF alpha, IL-1, IFN gamma, and IL-6. Endotoxin-induced production of inflammatory cytokines is augmented because the suppressive effects of IL-10 on inflammatory cytokine production from macrophages and neutrophils are completely abolished. The mice show a polarized immune response toward the Th1 type and develop chronic enterocolitis with age. Taken together, Stat3 plays a critical role in deactivation of macrophages and neutrophils mainly exerted by IL-10.

Dynamic Balance of pSTAT1 and pSTAT3 in C57BL/6 Mice Infected with Lethal Or Nonlethal Plasmodium yoelii

“…pSTAT3, which has antagonistic effect on pSTAT1 (27,28), plays a key role in suppressing the function of neutrophils, NK cells, DCs (31)(32)(33) and negatively regulating the Th1-mediated inflammatory response (30,31). Therefore, the balance of pSTAT1 and pSTAT3 plays an important role in regulating immune response and maintaining immunohomeostasis.…”

“…pSTAT3, which has antagonistic effect on pSTAT1 (27,28), is not only a potent negative regulator of the Th1-mediated inflammatory response, but also an activator of many genes that are crucial for immune regulation (29,30). Down-regulation of STAT3 could enhance Th1 type immune response and activate DCs, NK cells and macrophages (31)(32)(33). So the balance of pSTAT1 and pSTAT3, which has been studied in cancer immunity (31,34), has an important role in regulation of immune responses.…”

STAT‐1‐mediated repression of monocyte interleukin‐10 gene expression in vivo

“…Indeed, in data not shown, we demonstrate by chromatin immunoprecipitation that STAT-1 is physically associated with the IL-10 promoter at 16 h but not at 1 h following LPS challenge. Heterodimerization of STAT-1 with STAT-3 to mediate in vivo repression of IL-10 expression may play a role in the regulation of IL-10, as mice lacking STAT-3 in myeloid cells also overproduce IL-10 in response to LPS injection [29]. However, it is also possible that the observed effect is due to a different STAT that is activated in the course of LPS response only in the absence of STAT-1.…”

STAT3 in immune responses and inflammatory bowel diseases

“…Loss of STAT3 has been shown to increase sensitivities to apoptosis and certain defect in wound healing. Takeda et al [62] also deleted the STAT3 gene from macrophages and neutrophils by using the macrophagespecific lysozyme promoter. STAT3 ablation in these mice results in an increased sensitivity to endotoxin/LPS shock, chronic inflammation and chronic enterocolitis with age.…”

“…When IL-10-deficient mice are raised under germ-free conditions, IBD does not occur, indicating the importance of innate interactions. A seminal finding by Akira's group revealed that STAT3 is the mediator of IL-10 for immune suppression [62]. However, the detailed mechanism is unclear.…”