Rapamycin protects mice from staphylococcal enterotoxin B-induced toxic shock and blocks cytokine release in vitro and in vivo.
Staphylococcal enterotoxins are potent activators for human T cells and cause lethal toxic shock. Rapamycin, an immunosuppressant, was tested for its ability to inhibit staphylococcal enterotoxin B (SEB)-induced activation of human peripheral blood mononuclear cells (PBMC) in vitro and toxin-mediated shock in mice. Stimulation of PMBC by SEB was effectively blocked by rapamycin as evidenced by the inhibition of tumor necrosis factor alpha (TNF-alpha), interleukin 1beta (IL-1beta), IL-6, IL-2, gamma interferon (IFN-gamma), monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein 1alpha (MIP-1alpha), MIP-1beta, and T-cell proliferation. In vivo, rapamycin protected 100% of mice from lethal shock, even when administered 24 h after intranasal SEB challenge. The serum levels of MCP-1 and IL-6, after intranasal exposure to SEB, were significantly reduced in mice given rapamycin versus controls. Additionally, rapamycin diminished the weight loss and temperature fluctuations elicited by SEB.
Krakauer
Teresa
T
Dept. of Immunology, Bldg. 1425, USAMRIID, Fort Detrick, Frederick, MD 21702-5011, USA. teresa.krakauer@amedd.army.mil
Buckley
Marilyn
M
Issaq
Haleem J
HJ
Fox
Stephen D
SD
D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology; D016207:Cytokines / Q000037:antagonists & inhibitors*; D004768:Enterotoxins / Q000276:immunology / Q000633:toxicity*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000737:chemistry; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D012772:Shock, Septic / Q000188:drug therapy* / Q000276:immunology / Q000517:prevention & control; D020123:Sirolimus / Q000008:administration & dosage / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D016896:Treatment Outcome
D000900:Anti-Bacterial Agents; D016207:Cytokines; D004768:Enterotoxins; C031818:enterotoxin B, staphylococcal; D020123:Sirolimus