Toxicity of staphylococcal enterotoxins potentiated by lipopolysaccharide: major histocompatibility complex class II molecule dependency and cytokine release.
The biological effects of staphylococcal enterotoxins (SE), potentiated by bacterial lipopolysaccharide (LPS), were studied with mice. Control animals survived the maximum dose of either SE or LPS, while mice receiving both agents died. SEA was 43-fold more potent than SEB and 20-fold more potent than SEC1. The mechanism of toxicity was further examined with transgenic mice deficient in major histocompatibility complex class I or II expression. Class II-deficient mice were resistant to SEA or SEB. However, class I-deficient animals were less susceptible to SEA (30% lethality) than wild-type mice (93% lethality). In vitro stimulation of T cells from the three mouse phenotypes by SEA correlated well with toxicity. T cells from transgenic or wild-type mice were similarly responsive to SEA when presented by irradiated, wild-type mononuclear cells. These data confirmed that the toxicity of SE was mainly exerted through a mechanism dependent on the expression of major histocompatibility complex class II molecules. Toxicity was also linked to stimulated cytokine release. Levels in serum of tumor necrosis factor alpha, interleukin-6, and gamma interferon peaked 2 to 4 h after the potentiating dose of LPS but returned to normal within 10 h. Concentrations of interleukin-1 alpha were also maximal after 2 h but remained above the background for up to 22 h. Relative to the levels in mice given only SEA or LPS, the levels in serum of tumor necrosis factor alpha, interleukin-6, and gamma interferon increased 5-, 10-, and 15-fold, respectively, after injections of SEA plus LPS. There was only an additive effect of SEA and LPS on interleukin-1 alpha concentrations.
Stiles
B G
BG
Department of Immunology, U.S. Army Medical Research Institute of Infectious Diseases, Frederick, Maryland 21702-5011.
Bavari
S
S
Krakauer
T
T
Ulrich
R G
RG
D000818:Animals; D016207:Cytokines / Q000097:blood / Q000378:metabolism*; D004357:Drug Synergism; D004768:Enterotoxins / Q000008:administration & dosage / Q000633:toxicity*; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D007371:Interferon-gamma / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013211:Staphylococcus aureus / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016207:Cytokines; D004768:Enterotoxins; D000949:Histocompatibility Antigens Class II; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; C026066:enterotoxin A, Staphylococcal; D007371:Interferon-gamma