Control of Endotoxin Shock by the Dried Preparation of Low VirulentStreptococcus pyogenesOK-432

Abstract

Bacterial endotoxin, lipopolysaccharide (LPS), is a causative agent of Gram-negative septic shock. However, if preadministered at a low dose, LPS makes mice resistant to subsequent endotoxin challenge, the phenomenon known as LPS tolerance. Here we demonstrated that the pharmaceutical preparation of Gram-positiveStreptococcus pyogenes,OK-432, also induced a state analogous to LPS tolerance if administered 6–48 h prior to LPS challenge. The preadministration of OK-432 increased the lethal dose of LPS threefold in BDF1 mice, and this was accompanied by reduced gene expression of IL-6, IFN-γ, inducible nitric oxide synthase, and IL-10 in spleen and peritoneal cells. Serum concentrations of IL-6 and IFN-γ were also suppressed by the preadministration of OK-432. In contrast to the LPS tolerance, the levels of TNF-α mRNA were not suppressed in OK-432-administered mice, and their peritoneal cells produced high levels of TNF-α and soluble TNF receptor p75 in response to LPSin vitro.Peritoneal cells from OK-432 but not LPS-administered mice were hyporesponsive to IFN-γ in terms of nitric oxide synthesis, and this hyporesponsiveness to IFN-γ was abrogated by anti-IL-10 antibodies. Likewise, peritoneal cells from both OK-432- and LPS-administered mice were hyporesponsive to LPS, serum, TNF-α, IFN-γ, and PMA in terms of IL-6 production. Anti-IL-10 antibodies increased IL-6 production eightfold in cells from OK-432-administered mice, but marginally in cells from LPS-administered mice. Even in peritoneal cells from OK-432-administered mice, anti-IL-10 antibodies failed to fully restore IL-6 production. Thus, the hyporesponsive state of peritoneal cells was mediated by both IL-10-dependent and -independent mechanisms. These results demonstrated that OK-432 controlled endotoxin shock by blocking the cytokine cascade from TNF-α.