Injection time of interleukin-6 determines fatal outcome in experimental endotoxin shock.
Circulating interleukin-6 (IL-6) levels are directly correlated to fatal outcome in both patients and animal models with endotoxin shock. However, whether IL-6 is deleterious or protective in regard to survival is obscure. We investigated the action of IL-6 in the pathogenic progress of endotoxin shock. C3H/HeN mice received 10 micrograms of natural human IL-6 (Hu-IL-6) s.c. at various times before or after challenge with Escherichia coli lipopolysaccharide (LPS) at a lethal dose. Pretreatment with Hu-IL-6 0, 1, and 4 h before LPS administration improved the survival rate of the mice. However, no protection was observed when Hu-IL-6 was administered 24 h before or 1 h after the LPS injection. The protective mechanism of Hu-IL-6 pretreatment was not explained on the changes in the circulating levels of tumor necrosis factor and endogenous murine IL-6 (Mu-IL-6). The induction of fibrinogen and immunosuppressive acidic protein, a type of acute-phase proteins, may have contributed to the protection. The results show that the order and the time interval in which the administered Hu-IL-6 and the Mu-IL-6 induced by LPS act are the key to the determination of fatal outcome.
Yoshizawa
K
K
Basic Research Laboratories, Toray Industries Inc., Kanagawa, Japan.
Naruto
M
M
Ida
N
N
D000209:Acute-Phase Proteins / Q000096:biosynthesis; D000818:Animals; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007279:Injections, Subcutaneous; D015850:Interleukin-6 / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D012772:Shock, Septic / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy*; D013045:Species Specificity; D015996:Survival Rate; D016896:Treatment Outcome
D000209:Acute-Phase Proteins; D015850:Interleukin-6; D008070:Lipopolysaccharides