Overexpression of Interleukin‐15 Protects againstEscherichia coli–Induced Shock Accompanied by Inhibition of Tumor Necrosis Factor–α–Induced Apoptosis

Abstract

Interleukin (IL)-15, a potent inhibitor of tumor necrosis factor (TNF)-alpha-mediated apoptosis, causes multiple organ failure during endotoxic shock. We investigated the potential role of IL-15 in protection against Escherichia coli-induced shock by using IL-15 transgenic (Tg) mice. These mice were resistant to an otherwise lethal challenge with E. coli, although bacterial burden and serum levels of TNF-alpha were similar in non-Tg mice. Apoptosis in cells of the peritoneal cavity, liver, spleen, or lung was significantly suppressed in IL-15 Tg mice after E. coli infection. Peritoneal cells from naive IL-15 Tg mice were also resistant to TNF-alpha-induced apoptosis in vitro, and neutralization of endogenous IL-15 significantly aggravated TNF-alpha-induced apoptosis. Exogenous IL-15 prevented TNF-alpha-induced apoptosis in normal mice in vitro and improved the survival rate after E. coli challenge. These results suggest that IL-15 overexpression can prevent TNF-alpha-induced apoptosis and protect against E. coli-induced shock, indicating a possible therapeutic application of IL-15 for septic shock.

Interleukin-15 responses to aging and unloading-induced skeletal muscle atrophy

“…IL-15 administration in control mice also reduces the death rate from a lethal challenge of E. coli. The data further show that administration of IL-15 to isolated peritoneal cells in vitro prevented TNF-␣-induced apoptosis (23).…”

“…Multisystem apoptosis initiated in mice via treatment with an anti-Fas antibody was suppressed with injection of a longlasting IL-15-IgG 2b fusion protein (9). In addition, IL-15 transgenic mice are resistant to a lethal dose of Escherichia coli (23). IL-15 administration in control mice also reduces the death rate from a lethal challenge of E. coli.…”

Enhanced Dendritic Cell Survival Attenuates Lipopolysaccharide-Induced Immunosuppression and Increases Resistance to Lethal Endotoxic Shock

“…Consequently, IL-15-deficient mice are characterized by decreased DC numbers in blood and spleen, and transgenic overexpression of IL-15 in IL-15-deficient mice restores DC numbers (13). Under these conditions, IL-15 overexpression in mice is associated with enhanced survival following E. coli-induced septic shock (25). In this context, Flt3-L treatment, which enhances differentiation and mobilization of DCs, has been shown to suppress endotoxin-induced immunosuppression (26).…”

Systemic elevation of interleukin-15 in vivo promotes apoptosis in skeletal muscles of young adult and aged rats

“…into control mice also minimized the death rate from a lethal challenge of E. coli. These authors also demonstrated that IL-15 administration into isolated peritoneal cell cultures in vitro, prevented TNF-α induced apoptosis [13].…”