Control of endotoxin shock by the dried preparation of low virulent Streptococcus pyogenes OK-432.
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-positive Streptococcus 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-gamma, inducible nitric oxide synthase, and IL-10 in spleen and peritoneal cells. Serum concentrations of IL-6 and IFN-gamma were also suppressed by the preadministration of OK-432. In contrast to the LPS tolerance, the levels of TNF-alpha mRNA were not suppressed in OK-432-administered mice, and their peritoneal cells produced high levels of TNF-alpha and soluble TNF receptor p75 in response to LPS in vitro. Peritoneal cells from OK-432 but not LPS-administered mice were hyporesponsive to IFN-gamma in terms of nitric oxide synthesis, and this hyporesponsiveness to IFN-gamma was abrogated by anti-IL-10 antibodies. Likewise, peritoneal cells from both OK-432- and LPS-administered mice were hyporesponsive to LPS, serum, TNF-alpha, IFN-gamma, 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-alpha.
Division of Radiation Health, National Institute of Radiological Sciences, Chiba, Japan.
M
M
Nose
A
A
Uzawa
M
M
Nomura
Y
Y
Ikarashi
Y
Y
Nakata
M
M
Akashi
G
G
Suzuki
D000818:Animals; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000502:physiology; D015850:Interleukin-6 / Q000096:biosynthesis; D018950:Lipopolysaccharide Receptors / Q000032:analysis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D010844:Picibanil / Q000627:therapeutic use*; D012772:Shock, Septic / Q000209:etiology / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D015850:Interleukin-6; D018950:Lipopolysaccharide Receptors; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D009569:Nitric Oxide; D010844:Picibanil; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse