Toxic shock syndrome (TSS) is an acute, serious systemic illness caused by bacterial superantigens (BSAg). Non-availability of a suitable animal model until recently has hampered an in-depth understanding of the pathogenesis of TSS. In the current study, we characterized the early molecular events underlying TSS using our HLA-DR3 transgenic mouse model. Gene expression profiling using DNA microarrays identified a rapid and significant upregulation of several pro- as well as anti-inflammatory mediators, many of which have never been previously described in TSS. In vivo administration of SEB led to an increase in the expression of Th0- (IL-2, 240-folds); Th1- (IFN-, 360-folds and IL-12, 8-folds); Th2- (IL-4, 53-folds and IL-5, 4-folds) as well as Th17-type cytokines (IL-21, 19-folds and IL-17, 5-folds). The immunoregulatory cytokines (IL-6, 700-folds and IL-10, 18-folds); CC chemokines (such as CCL 2, 11, 3, 24, 17, 12, 7), CXC chemokines (such as CXCL 1, 2, 5, 11, 10, 19); and several proteases (Matrix metalloproteinases 13, 8, 3 and 9) were also upregulated. Serum levels of several of these cytokines/chemokines were also significantly elevated. Pathway analyses revealed significant modulation in a variety of biochemical and cellular functions, providing molecular insights into the pathogenesis of TSS. Administration of bortezomib, a clinically approved proteasome inhibitor capable of blocking NFB pathway, was able to significantly modulate the expression of a variety of genes induced by SEB. Thus, our study showed that TSS is a complex process and emphasized the potential of use of bortezomib in the therapy of superantigen-induced TSS.