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Prolonged survival of mice with Pseudomonas aeruginosa-induced sepsis by rIL-12 modulation of IL-10 and interferon-

Department of Laboratory Medicine and *Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki 852-8501, Japan

Corresponding author: Dr T. Yamaguchi (e-mail: toshi-ngs{at}umin.ac.jp).

Received 12 Aug. 1999; revised version accepted 14 Jan. 2000.

Abstract

Interleukin-12 (IL-12) is thought to play an important role as a modulator of levels of IL-10 and interferon- (IFN-). To address the therapeutic effects of rIL-12 in an endogenous sepsis model in mice, which closely mimics the pathophysiology of septicaemia in man, the effects of rIL-12 on the levels of cytokines such as IL-10 and IFN-, and on the survival of septic mice infected with Pseudomonas aeruginosa PAO1 were examined. First, in the endogenous sepsis model, the serum levels of IFN- and IL-10 remained normal until days 8 and 10, respectively, when significant rises were seen. On day 11, levels of IFN- returned to normal, but levels of IL-10 remained high. Interestingly, the IL-10 serum level reached a maximum 2 days later than the IFN- serum level. In the light of these results, septic mice were given 0.01 µg of rIL-12 by intraperitoneal injection and the serum levels of endogenous cytokines and the survival times were examined. Mice treated with rIL-12 on days 5, 6 and 7 after infection survived significantly longer than control septic mice treated with saline only. Treatment with rIL-12 also led to a significant increase of the serum IFN- level and a decrease of the serum IL-10 level on day 11. These results suggest that rIL-12 exerts therapeutic activity against endogenous sepsis caused by P. aeruginosa by stimulating pro-inflammatory responses and attenuating anti-inflammatory responses.

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