Akt Decreases Lymphocyte Apoptosis and Improves Survival in Sepsis

Abstract

Sepsis induces extensive death of lymphocytes that may contribute to the immunosuppression and mortality of the disorder. The serine/threonine kinase Akt is a key regulator of cell proliferation and death. The purpose of this study was to determine whether overexpression of Akt would prevent lymphocyte apoptosis and improve survival in sepsis. In addition, given the important role of Akt in cell signaling, T cell Th1 and Th2 cytokine production was determined. Mice that overexpress a constitutively active Akt in lymphocytes were made septic, and survival was recorded. Lymphocyte apoptosis and cytokine production were determined at 24 h after surgery. Mice with overexpression of Akt had a marked improvement in survival compared with wild-type littermates, i.e., 94 and 47% survival, respectively, p < 0.01. In wild-type littermates, sepsis caused a marked decrease in IFN-γ production, while increasing IL-4 production >2-fold. In contrast, T cells from Akt transgenic mice had an elevated production of IFN-γ at baseline that was maintained during sepsis, while IL-4 had little change. Akt overexpression also decreased sepsis-induced lymphocyte apoptosis via a non-Bcl-2 mechanism. In conclusion, Akt overexpression in lymphocytes prevents sepsis-induced apoptosis, causes a Th1 cytokine propensity, and improves survival. Findings from this study strengthen the concept that a major defect in sepsis is impairment of the adaptive immune system, and suggest that strategies to prevent lymphocyte apoptosis represent a potential important new therapy.

Incremental expression of Tlr4 correlates with mouse resistance to Salmonella infection and fine regulation of relevant immune genes

“…26 The mechanism underlying lymphocyte depletion during sepsis is believed to be apoptosis, and treatment with apoptosis inhibitor or use of mice with genetic modifications rendering them less susceptible to apoptosis improves survival from polymicrobial sepsis. 27,28 It is conceivable that sepsis-induced apoptosis could contribute to the failure of our mice to resolve the infection. In addition, we also observed a drop in Il12b expression on day 8, below the level of expression seen in non-infected mice.…”

α-Lipoic acid attenuates LPS-induced inflammatory responses by activating the phosphoinositide 3-kinase/Akt signaling pathway

“…The PI3K/Akt pathway is a conserved family of signal transduction enzymes that are involved in regulating cellular proliferation and survival. A growing body of evidence suggests that the PI3K/Akt pathway plays an important role as a negative feedback regulator of excessive innate immune and Toll-like receptor-mediated proinflammatory responses (15)(16)(17)(18)(19)(20)(21)(22). Hence, inhibition of PI3K/Akt signaling enhanced LPS-induced activation of NF-B and AP-1 and gene expression of TNF␣ and tissue factor in cultured cells (15).…”

“…Activation of the PI3K/Akt pathway improves survival and protects against septic death in experimental animals (17,19,20,31). Therefore, we investigated whether LA could protect against LPS-induced endotoxemic shock and lethality.…”

“…Conversely, activation of the PI3K/Akt pathway by glucan phosphate (17) or angiopoietin-1 (18) inhibited TNF␣-induced tissue factor expression in endothelial cells (18) and was correlated with increased survival in a cecal ligation and puncture (CLP) septic mouse model (17). Furthermore, transgenic overexpression of Akt has been shown to protect against septic death in the CLP mouse model (19) as well as mice infected with the Gram-negative bacterium Francisella (20). Recent studies have shown that Akt dampens LPS-induced NF-B activation by phosphorylating and, hence, inactivating glycogen synthase kinase (GSK) 3␤, which negatively regulates its downstream target, NF-B, and potently suppresses LPSinduced proinflammatory responses and endotoxic shock (15,22).…”

“…The phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway has been shown to play an important role in negatively regulating LPS-induced acute inf lammatory responses in vitro and in vivo (15)(16)(17)(18)(19)(20)(21). Inhibition of PI3K/Akt signaling enhances LPS-induced activation of NF-B, AP-1, and Egr-1 transcription factors and gene expression of TNF␣ and tissue factor in cultured human monocytic cells (15).…”