Abstract
The egcSEs comprise five genetically linked staphylococcal enterotoxins, SEG, SEI, SElM, SElN, and SElO and two pseudotoxins which constitute an operon present in up to 80% of Staphylococcus aureus isolates. A preparation containing these proteins was recently used to treat advanced lung cancer with pleural effusion. We investigated the hypothesis that egcSEs induce nitric oxide (NO) and associated cytokine production and that these agents may be involved in tumoricidal effects against a broad panel of clinically relevant human tumor cells. Preliminary studies showed that egcSEs and SEA activated T cells (range: 11–25%) in a concentration dependent manner. Peripheral blood mononuclear cells (PBMCs) stimulated with equimolar quantities of egcSEs expressed NO synthase and generated robust levels of nitrite (range: 200–250 μM), a breakdown product of NO; this reaction was inhibited by NG-monomethyl-L-arginine (L-NMMA) (0.3 mM), an NO synthase antagonist. Cell free supernatants (CSFs) of all egcSE-stimulated PBMCs were also equally effective in inducing concentration dependent tumor cell apoptosis in a broad panel of human tumor cells. The latter effect was due in part to the generation of NO and TNF-α since it was significantly abolished by L-NMMA, anti-TNF-α antibodies, respectively, and a combination thereof. A hierarchy of tumor cell sensitivity to these CFSs was as follows: lung carcinoma > osteogenic sarcoma > melanoma > breast carcinoma >neuroblastoma. Notably, SEG induced robust activation of NO/TNFα-dependent tumor cell apoptosis comparable to the other egcSEs and SEA despite TNF-α and IFN-γ levels that were 2 and 8 fold lower, respectively, than the other egcSEs and SEA. Thus, egcSEs produced by S. aureus induce NO synthase and the increased NO formation together with TNF-α appear to contribute to egcSE-mediated apoptosis against a broad panel of human tumor cells.
Highlights
Staphylococcus aureus produces a broad range of exoproteins, including staphylococcal enterotoxins and staphylococcal-like enterotoxins (SEs and SEls; respectively)
We investigated the ability of SEA and our recombinant egcSEs to activate CD69 expression in T cells obtained from 3 healthy donors
Our results demonstrate that egcSEs activate 11–21% or resting T cells and that cell free supernatants (CFSs) from egcSE-stimulated Peripheral blood mononuclear cells (PBMCs) induced nitric oxide (NO) synthase activation and robust generation of NO along with TH-I TH-2 cytokines
Summary
Staphylococcus aureus produces a broad range of exoproteins, including staphylococcal enterotoxins and staphylococcal-like enterotoxins (SEs and SEls; respectively). All these toxins share superantigenic properties by stimulating a large proportion of T cells after binding to the major histocompatibility complex (MHC) class II molecule and crosslinking specific vβ regions of the T-cell receptor (TCR) This interaction results in polyclonal T-cell activation and massive secretion of cytokines such as interleukin-2 (IL)-2, interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), and nitric oxide (NO) (Marrack and Kappler, 1990). The egcSEs are structurally homologous and phylogenetically related to classic SEA-E and exhibit unique vβ signatures (Jarraud et al, 2001) Despite their prevalence and Frontiers in Cellular and Infection Microbiology www.frontiersin.org egcSEs induced tumor cell apoptosis broad distribution, human serum levels of neutralizing antibodies directed against the egcSEs are significantly lower than those directed to the classic SEs (Holtfreter et al, 2004). Septicemia associated with the egcSEs has been reported to be less severe clinically than that linked to the classic SEs (Ferry et al, 2008)
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