Abstract
Staphylococcal enterotoxin B (SEB) is a potent superantigen capable of inducing inflammation characterized by robust immune cell activation and proinflammatory cytokine release. Exposure to SEB can result in food poisoning as well as fatal conditions such as toxic shock syndrome. In the current study, we investigated the effect of natural indoles including indole-3-carbinol (I3C) and 3,3’-diindolylmethane (DIM) on SEB-mediated liver injury. Injection of SEB into D-galactosamine-sensitized female C57BL/6 mice resulted in liver injury as indicated by an increase in enzyme aspartate transaminase (AST) levels, induction of inflammatory cytokines, and massive infiltration of immune cells into the liver. Administration of I3C and DIM (40mg/kg), by intraperitonal injection, attenuated SEB-induced acute liver injury, as evidenced by decrease in AST levels, inflammatory cytokines and cellular infiltration in the liver. I3C and DIM triggered apoptosis in SEB-activated T cells primarily through activation of the intrinsic mitochondrial pathway. In addition, inhibitor studies involving caspases revealed that I3C and DIM-mediated apoptosis in these activated cells was dependent on caspase-2 but independent of caspase-8, 9 and 3. In addition, I3C and DIM caused a decrease in Bcl-2 expression. Both compounds also down-regulated miR-31, which directly targets caspase-2 and influences apoptosis in SEB-activated cells. Our data demonstrate for the first time that indoles can effectively suppress acute hepatic inflammation caused by SEB and that this may be mediated by decreased expression of miR-31 and consequent caspase-2-dependent apoptosis in T cells.
Highlights
Staphylococcal enterotoxin B (SEB) is a toxic superantigen (SAG) and major virulence factor secreted by the bacterium Staphylococcus aureus (S. aureus), which causes nosocomial infections and community acquired diseases [1,2]
SEB is classified as aSAG because it bypasses normal processing by antigen-presenting cells (APCs), but instead interacts outside of the peptide-binding groove of major histocompatibility complex class II (MHC II) molecules with certain external Vβ domains located on T cell receptors (TCR)
Injection of SEB into Dgal-sensitized mice resulted in an increase in aspartate transaminase (AST) levels in sera collected at 8 hours, an indication of acute liver injury
Summary
Staphylococcal enterotoxin B (SEB) is a toxic superantigen (SAG) and major virulence factor secreted by the bacterium Staphylococcus aureus (S. aureus), which causes nosocomial infections and community acquired diseases [1,2]. SEB is classified as aSAG because it bypasses normal processing by antigen-presenting cells (APCs), but instead interacts outside of the peptide-binding groove of major histocompatibility complex class II (MHC II) molecules with certain external Vβ domains located on T cell receptors (TCR). This results in rapid T cell activation without regard to antigen specificity [6,7]. A more effective treatment would involve controlling the rapid T cell activation and cytokine storm by the virulent factors produced by S. aureus, such as SEB
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