IFN-GAMMA INVOLVEMENT IN THE SEVERITY OF GRAM-NEGATIVE INFECTIONS IN MICE

The role of IFN-gamma in the regulation of inflammation leading to gra m-negative septic shock is still poorly understood. IFN-gamma blockade has been shown to improve the survival of animals challenged with i.v . bolus injections of LPS and gram-negative bacteria. We have investig ated a model of focal Escherichia coli infection leading to peritoniti s and septic shock. Mice were challenged i.p. with an inoculum near th e LD50. The addition of rIFN-gamma together with bacteria increased th e mortality and the level of blood TNF-alpha and IL-6. Conversely bloc kade of IFN-gamma with a neutralizing mAb significantly improved the s urvival of the mice. This beneficial effect was not associated with a stringent decrease in blood bacterial counts and TNF-alpha and IL-6 le vels in survivors. In this model, the protective effect of anti-IFN-ga mma mAb contrasted with the ineffectiveness of a neutralizing anti-TNF -alpha mAb. These findings suggest that overproduction of IFN-gamma mi ght have a more detrimental role than overproduction of TNF-alpha duri ng focal gram-negative infections.