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Inhibition of ROS and upregulation of inflammatory cytokines by FoxO3a promotes survival against Salmonella typhimurium.

ABSTRACT: Virulent intracellular pathogens, such as the Salmonella species, engage numerous virulence factors to subvert host defence mechanisms to induce a chronic infection that leads to typhoid or exacerbation of other chronic inflammatory conditions. Here we show the role of the forkhead transcription factor FoxO3a during infection of mice with Salmonella typhimurium (ST). Although FoxO3a signalling does not affect the development of CD8(+) T cell responses to ST, FoxO3a has an important protective role, particularly during the chronic stage of infection, by limiting the persistence of oxidative stress. Furthermore, FoxO3a signalling regulates ERK signalling in macrophages, which results in the maintenance of a proinflammatory state. FoxO3a signalling does not affect cell proliferation or cell death. Thus, these results reveal mechanisms by which FoxO3a promotes host survival during infection with chronic, virulent intracellular bacteria.

SUBMITTER: Joseph J

PROVIDER: S-EPMC5023958 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Inhibition of ROS and upregulation of inflammatory cytokines by FoxO3a promotes survival against Salmonella typhimurium.

Joseph Julie J Ametepe Emmanuelle S ES Haribabu Naveen N Agbayani Gerard G Krishnan Lakshmi L Blais Alexandre A Sad Subash S

Nature communications 20160907

Virulent intracellular pathogens, such as the Salmonella species, engage numerous virulence factors to subvert host defence mechanisms to induce a chronic infection that leads to typhoid or exacerbation of other chronic inflammatory conditions. Here we show the role of the forkhead transcription factor FoxO3a during infection of mice with Salmonella typhimurium (ST). Although FoxO3a signalling does not affect the development of CD8(+) T cell responses to ST, FoxO3a has an important protective ro ...[more]

PMID: 27599659

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Project description:Salmonellosis in broilers is not merely a significant disease with high economic costs in the poultry industry but also the foodborne disease with the impact on public health by cross-contamination. This study was to investigate the prebiotic ability of trehalose supplementing in diets (0, 1, 3, and 5%, w/w) against Salmonella by using S. Typhimurium (ST)-inoculated broilers. The improvements (P < 0.05) of feed conversion ratio (FCR) were observed with 5% trehalose supplementation in ST-inoculated broilers' diets. An addition of 3 or 5% trehalose in diets increased (P < 0.05) the abundance of lactobacilli in the duodenum and jejunum but decreased (P < 0.05) the growth of ST in the cecum. The adverse effects on serum levels of aspartate aminotransferase, triglyceride, and albumin and globulin ratio in ST-inoculated broilers were noticed and counteracted by supplementing 3 or 5% trehalose in diets (P < 0.05). Besides, the inclusion of trehalose in diets alleviated the intestinal damages and maintained the integrity of cecal epithelial cells after ST challenge under an haematoxylin and eosin-staining observation. Supplementing trehalose further showed the inhibitions of toll-like receptor 4-mediated nuclear factor-kappa-B pathway, including the downregulation (P < 0.05) of proinflammatory cytokine genes, such as interleukin 1 beta and lipopolysaccharide-induced tumor necrosis factor-alpha factor and the upregulation (P < 0.05) of interleukin 10 and interferon-alpha in ST-inoculated broilers. Overall, supplementing trehalose alleviated the adverse effects from ST challenge on FCR, serum biochemistry, the damage, and inflammation in the liver and cecum. Those improvements on ST challenged broilers also contributed to the overgrowth of lactobacilli, the decrement of ST, and anti-inflammatory effects in affected broilers. Trehalose, therefore, could be a promising prebiotic against salmonellosis to benefit broiler production and promote food safety in the poultry industry.

Project description:BackgroundPeripheral serotonin is involved in tumorigenesis and induces a pro-proliferative effect in hepatocellular carcinoma (HCC) cells; however, the intracellular mechanisms by which serotonin exerts a mitogenic effect remain unclear. In this research, we examined whether FOXO3a, a transcription factor at the interface of crucial cellular processes, plays a role downstream of serotonin in HCC cells.ResultsThe cell viability and expression of FOXO3a was assessed in three HCC cell lines (Huh7, HepG2 and Hep3B) during serum deprivation in the presence or absence of serotonin. Serum free media significantly inhibited HCC proliferation and led to reduced expression and nuclear accumulation of FOXO3a. Knockdown of FOXO3a enhanced the ability of serum deprivation to inhibit HCC cells proliferation. And overexpression of non-phosphorylated FOXO3a in HCC cells reversed serum-deprivation-induced growth inhibition. Serotonin reversed the serum-deprivation-induced inhibition of cell proliferation and upregulated FOXO3a in Huh7 cells; however, serotonin had no effect on the proliferation of serum-deprived HepG2 or Hep3B cells. In addition to proliferation, serotonin also induced phosphorylation of AKT and FOXO3a in serum-deprived Huh7 cells but not in HepG2 and Hep3B cells. However, the phosphorylation of FOXO3a induced by serotonin did not export FOXO3a from nucleus to cytoplasm in serum-deprived Huh7 cells. Consequently, we demonstrated that serotonin promoted the proliferation of Huh7 cells by increasing the expression of FOXO3a. We also provide preliminary evidence that different expression levels of the 5-HT2B receptor (5-HT2BR) may contribute to the distinct effects of serotonin in different serum-deprived HCC cells.ConclusionsThis study demonstrates that FOXO3a functions as a growth factor in serum-deprived HCC cells and serotonin promotes the proliferation of serum-deprived HCC cells via upregulation of FOXO3a, in the presence of sufficient levels of the serotonin receptor 5-HT2BR. Drugs targeting the serotonin-5-HT2BR-FOXO3a pathway may provide a novel target for anticancer therapy.

Dataset Information

Inhibition of ROS and upregulation of inflammatory cytokines by FoxO3a promotes survival against Salmonella typhimurium.

Publications

Inhibition of ROS and upregulation of inflammatory cytokines by FoxO3a promotes survival against Salmonella typhimurium.

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