Temporal sequence and kinetics of proinflammatory and anti-inflammatory cytokine secretion induced by toxic shock syndrome toxin 1 in human peripheral blood mononuclear cells

The staphylococcal superantigen toxic shock syndrome toxin 1 (TSST-1) induc es massive cytokine production, which is believed to be the key factor in t he pathogenesis of TSS. The temporal sequence and kinetics of both proinfla mmatory and anti-inflammatory cytokines induced by TSST-1 in human peripher al blood mononuclear cells were investigated. A panel of loss-of-function s ingle-amino-acid-substitution mutants of TSST-1, previously demonstrated to be defective in either major histocompatibility complex (MHC) class II bin ding (G31R) or T-cell receptor (TCR) interaction (H135A, S14N), was studied in parallel to further elucidate the mechanisms of cytokine secretion. Wil d-type recombinant (WT r) TSST-1 induced a biphasic pattern of cytokine sec retion: an early phase with rapid release of proinflammatory cytokines (esp ecially gamma interferon, interleukin-2 [IL-2], and tumor necrosis factor a lpha [TNF-alpha]) within 3 to 4 h poststimulation, and a later phase with m ore gradual production of both proinflammatory (IL-1 beta, IL-12, and TNF-b eta) and antiinflammatory (IL-6, IL-10) cytokines within 16 to 72 h poststi mulation. G31R, which is defective in MHC class II binding, induced a cytok ine profile similar to that of WT rTSST-1, except that secretion of the ear ly-phase proinflammatory cytokines was delayed and production of IL-1 beta and IL-12 was markedly reduced. In contrast, mutant toxins defective in TCR interaction either demonstrated complete absence of any cytokine secretion during the entire observation period (H135A) or resulted in complete aboli shment of IL-2 and other early-phase proinflammatory cytokines, while secre tion of IL-10 appeared unaffected (S14N). Neither WT rTSST-1 nor the mutant toxins induced IL-4 or transforming growth factor beta. Our data indicate that effective TCR interaction is critical for the induction of the early-p hase proinflammatory cytokine response, thus underscoring the importance of T-cell signaling in TSS.