Prolonged survival of mice with Pseudomonas aeruginosa-induced sepsis by rIL-12 modulation of IL-10 and interferon-gamma.
Interleukin-12 (IL-12) is thought to play an important role as a modulator of levels of IL-10 and interferon-gamma (IFN-gamma). 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-gamma, 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-gamma and IL-10 remained normal until days 8 and 10, respectively, when significant rises were seen. On day 11, levels of IFN-gamma 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-gamma serum level. In the light of these results, septic mice were given 0.01 microg 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-gamma 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 proinflammatory responses and attenuating anti-inflammatory responses.
Toshiyuki
T
Yamaguchi
Yoichi
Y
Hirakata
Koichi
K
Izumikawa
Yoshitsugu
Y
Miyazaki
Department of Laboratory Medicine and *Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki 852-8501, Japan.
Shigefumi
S
Maesaki
Department of Laboratory Medicine and *Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki 852-8501, Japan.
Kazunori
K
Tomono
Yasuaki
Y
Yamada
Department of Laboratory Medicine and *Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki 852-8501, Japan.
Shigeru
S
Kohno
Shimeru
S
Kamihira
D000818:Animals; D016470:Bacteremia / Q000401:mortality*; D007371:Interferon-gamma / Q000097:blood*; D016753:Interleukin-10 / Q000097:blood*; D018664:Interleukin-12 / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D011552:Pseudomonas Infections / Q000401:mortality*; D011994:Recombinant Proteins / Q000627:therapeutic use
D011994:Recombinant Proteins; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma