Changes of Foxo3a in PBMCs and its associations with stress hyperglycemia in acute obstructive suppurative cholangitis patients.

ABSTRACT

OBJECTIVE: The levels of Foxo3a in the peripheral blood mononuclears cells (PBMCs) before and after treatment were detected in acute obstructive suppurative cholangitis (AOSC) patients to evaluate the associations between Foxo3a and stress hyperglycemia (SHG). METHODS: PBMCs were obtained from AOSC patients (n=28) on admission (AP), from patients at 1 week after cure (RP) and from healthy volunteers (HV) (n=14) to evaluate the relationship between the protein levels of Foxo3a and the serum levels of glucose. Signaling pathways, which link inflammation and glycometabolism, simultaneously affecting the expression of Foxo3a, were detected. In addition, cytokines were detected in PBMCs and AOSC mouse models, which were pre-treated with Foxo3a agonist. RESULTS: The levels of glucose and p-Foxo3a in the AP were significantly higher than those in the RP and HV, where as the levels of Foxo3a in the AP were lower than those in the RP and HV. Foxo3a levels in the AP normalized against RP were strongly negatively correlated with the glucose levels in the AP normalized against RP. The levels of sphingosine-1-phosphate receptor 2 (S1PR2) in the AP were higher than those in the RP and HV. In addition, inhibition of Foxo3a phosphorylation, coupled with the down-regulation of S1PR2, attenuated the LPS-induced inflammatory response in the PBMCs and AOSC mouse models. CONCLUSIONS: Foxo3a is correlated with the dysregulation of glucose homeostasis in the pathogenesis of AOSC-induced sepsis by inhibiting the activation of PI3K/Akt-S1PR2 and NF-κB pathways, hinting at a switched role and therapeutic potentialities in the early stage of sepsis.