Detrimental effect of the proteasome inhibitor, bortezomib in bacterial superantigen- and lipopolysaccharide-induced systemic inflammation.
Bacterial superantigen (BSAg)-induced toxic shock syndrome (TSS) and bacterial lipopolysaccharide (LPS)-induced shock are characterized by severe systemic inflammation. As nuclear factor kappaB (NF kappaB) plays an important role in inflammation and bortezomib, a proteasome inhibitor widely used in cancer chemotherapy, is a potent inhibitor of NF kappaB activation, we evaluated the therapeutic and prophylactic use of bortezomib in these conditions using murine models. Bortezomib prophylaxis significantly reduced serum levels of many cytokines and chemokines induced by BSAg. However, at 3 hours, serum level of TNF-a, an important cytokine implicated in TSS, was significantly reduced but not abolished. At 6 hours, there was no difference in the serum TNF-a levels between bortezomib treated and untreated mice challenged with staphylococcal enterotoxin B (SEB). Paradoxically, all mice treated with bortezomib either before or after BSAg challenge succumbed to TSS. Neither bortezomib nor BSAg was lethal if given alone. Serum biochemical parameters and histopathological findings suggested acute liver failure as the possible cause of mortality. Liver tissue from SEB-challenged mice treated with bortezomib showed a significant reduction in NF kappaB activation. Because NF kappaB-dependent antiapoptotic pathways protect hepatocytes from TNF-alpha-induced cell death, inhibition of NF kappaB brought forth by bortezomib in the face of elevated TNF-alpha levels caused by BSAg or LPS is detrimental.
Tilahun
Ashenafi Y
AY
Department of Immunology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
Theuer
Jayne E
JE
Patel
Robin
R
David
Chella S
CS
Rajagopalan
Govindarajan
G
D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D001897:Boronic Acids / Q000009:adverse effects*; D000069286:Bortezomib; D015853:Cysteine Proteinase Inhibitors / Q000009:adverse effects*; D016207:Cytokines / Q000096:biosynthesis; D015803:HLA-DR3 Antigen / Q000235:genetics; D008070:Lipopolysaccharides / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000009:adverse effects*; D018089:Superantigens / Q000633:toxicity*; D018746:Systemic Inflammatory Response Syndrome / Q000139:chemically induced*
D001897:Boronic Acids; D015853:Cysteine Proteinase Inhibitors; D016207:Cytokines; D015803:HLA-DR3 Antigen; D008070:Lipopolysaccharides; D016328:NF-kappa B; D061988:Proteasome Inhibitors; D011719:Pyrazines; D018089:Superantigens; C067713:lactacystin; D000069286:Bortezomib; D000111:Acetylcysteine