Critical role of Kupffer cell-derived IL-10 for host defense in septic peritonitis

Intra-abdominal infection in patients following major visceral surgery is a ssociated with high mortality. Using a macrophage depletion technique, we d emonstrate that in murine septic peritonitis, Kupffer cells are a major sou rce of systemic IL-10 levels. Kupffer cell-depleted mice were highly suscep tible to the lethal effects of septic peritonitis and exhibited an increase d bacterial load. Kupffer cell-depleted mice were protected by the administ ration of an IL-10-Fc fusion protein. Loss of Kupffer cell-derived IL-10 wa s associated with a weak increase in serum IL-12 levels, whereas TNF, IL-1 alpha, and IL-18 levels were not significantly elevated, suggesting that th e loss of Kupffer cell-derived IL-10 did not result in a toxic cytokine rel ease syndrome. Instead, loss of Kupffer cell-derived IL-10 was associated w ith a reduced splenocyte production of IFN-gamma that is required for immun e protection in murine septic peritonitis. Therefore, the results suggest t hat the protective function of IL-10 in septic peritonitis may not be restr icted to the anti-inflammatory activities of IL-10.