Therapeutic use of proteasome inhibitors in bacterial superantigen- and LPS-induced acute systemic inflammatory response syndromes (93.13)

Abstract

Abstract Bacterial superantigen-induced toxic shock syndrome (TSS) and sepsis are characterized by a profound systemic inflammatory response. Given the important role of NF¿B pathway in inflammation, we investigated whether a clinically approved proteasome inhibitor, Bortezomib, capable of inhibiting NF¿B pathway, be of therapeutic use in such conditions using HLA class II transgenic mice. Bortezomib significantly blocked staphylococcal enterotoxin B (SEB)-induced T cell activation and cytokine production in vitro. In SEB-induced TSS, in vivo administration of Bortezomib significantly reduced serum levels of several pro-inflammatory cytokines and chemokines. Nevertheless, 100% of SEB challenged mice treated with Bortezomib succumbed to TSS, and Bortezomib sensitized mice to TSS at concentrations of SEB which are otherwise non-lethal (i.e., as low as 2 μg/mouse), even when administered 24 hours after exposure to SEB. Sensitization to TSS by Bortezomib was not due to the pro-apoptotic effects of Bortezomib. Serum biochemical parameters and histopathological findings suggested acute liver failure as the possible cause of mortality. In sepsis model, whereas LPS alone (10 μg/mouse) was seldom lethal, it was uniformly lethal when administered along with Bortezomib. In conclusion, Bortezomib sensitizes mice to certain acute systemic inflammatory diseases. Supported by R01AI068741 and AI 72211