Toll-like receptor 2 deficiency relieves splenic immunosuppression during sepsis.

Immunosuppression is associated with long-term mortality during sepsis. However, the underlying mechanism of immunosuppression remains poorly understood. Toll-like receptor 2 (TLR2) contributes to sepsis pathogenesis. We sought to determine the role of TLR2 in immunosuppression in the spleen during polymicrobial sepsis. Using an experimental model of polymicrobial sepsis induced by cecal ligation and puncture (CLP), we measured the expression of inflammatory cytokines and chemokines in spleen 6 and 24 h after CLP to evaluate the immune response, and compared the expression of inflammatory cytokines and chemokines, apoptosis, and intracellular ATP production in spleen of wild-type (WT) and TLR2-deficient (TLR2-/-) mice 24 h after CLP. We found that pro-inflammatory cytokines and chemokines, such as TNF-α and IL-1ß peaked 6 h after CLP, while IL-10, an anti-inflammatory cytokine, peaked 24 h after CLP in the spleen. At this later time point, TLR2-/- mice presented decreased levels of IL-10 and decreased caspase 3 activation but no significant difference in intracellular ATP production in spleen compared to WT mice. Our data imply that TLR2 has a pronounced effect on sepsis-induced immunosuppression in spleen.

TBC1D8 Amplification Drives Tumorigenesis through Metabolism Reprogramming in Ovarian Cancer.

Cancer cells undergo metabolic reprogramming to support their energy demand and biomass synthesis. However, the mechanisms driving cancer metabolism reprogramming are not well understood. Methods: The differential proteins and interacted proteins were identified by proteomics. Western blot, qRT-PCR and IHC staining were used to analyze TBC1D8 levels. In vivo tumorigenesis and metastasis were performed by xenograft tumor model. Cross-Linking assays were designed to analyze PKM2 polymerization. Lactate production, glucose uptake and PK activity were determined. Results: We established two aggressive ovarian cancer (OVCA) cell models with increased aerobic glycolysis. TBC1D8, a member of the TBC domain protein family, was significantly up-regulated in the more aggressive OVCA cells. TBC1D8 is amplified and up-regulated in OVCA tissues. OVCA patients with high TBC1D8 levels have poorer prognoses. TBC1D8 promotes OVCA tumorigenesis and aerobic glycolysis in a GAP activity-independent manner in vitro and in vivo. TBC1D8 bound to PKM2, not PKM1, via its Rab-GAP TBC domain. Mechanistically, TBC1D8 binds to PKM2 and hinders PKM2 tetramerization to decreases pyruvate kinase activity and promote aerobic glycolysis, and to promote the nuclear translocation of PKM2, which induces the expression of genes which are involved in glucose metabolism and cell cycle. Conclusions:TBC1D8 drives OVCA tumorigenesis and metabolic reprogramming, and TBC1D8 serves as an independent prognosis factor for OVCA patients.