Interferon-gamma inhibition attenuates lethality after cecal ligation and puncture in rats: implication of high mobility group box-1.

Interferon (IFN)-gamma is an important immunomodulatory agent that is stimulated during infection to aid in host defense. However, increased IFN-gamma levels have been implicated as a mediator in various models of tissue injury and endotoxemia. We have previously shown that inhibition of IFN-gamma decreased bacterial load by accelerating peritoneal fibrin deposition in the cecal ligation and puncture (CLP) model of peritonitis. In addition, circulating inflammatory mediators such as interleukin (IL)-6 were reduced by IFN-gamma inhibition. In the present study, we show that administration of IFN-gamma antibody (1.2 mg/kg, i.v.) attenuated mortality after CLP. Administration of this antibody was able to reduce mortality when given immediately after CLP or 24 h after CLP surgery. Mortality in sepsis has been closely associated with increased release of high mobility group box-1 (HMGB1). Furthermore, it has been reported that IFN-gamma stimulates the release of HMGB1 from macrophages. Our studies showed that inhibition of IFN-gamma activity in vivo reduced the levels of HMGB1 in peritoneal fluid and serum of CLP rats 24 h after surgery. In addition, the decrease in HMGB1 was associated with an increase in tissue repair as evidenced by histological analyses. These results suggest that the attenuation of mortality in IFN-gamma antibody-treated rats was associated with a decrease in HMGB1 release.