Excessive release of proinflammatory cytokines from cells stimulated with lipopolysaccharide (LPS) or staphylococcal exotoxin (SE) mediates the pathophysiologic manifestations of septic shock. Tricyclodecan-9-yl (D609), an inhibitor of phosphatidylcholine-specific phospholipase C, suppressed LPS-or SE-induced cytokines and chemokines in human peripheral blood mononuclear cells. These data suggest a potential role for D609 in the treatment of septic shock.Lipopolysaccharide (LPS) and staphylococcal exotoxins (SE) are among the most common etiological agents causing septic shock (2,10,18). Although these bacterial products interact with host cells through different receptors, they trigger excessive systemic release of inflammatory cytokines, resulting in septic shock. LPS from gram-negative bacteria binds to serum LPS-binding protein, which then facilitates its binding to the cell surface protein CD14 on monocytes/macrophages and other cells (21). The subsequent interaction of LPS-CD14 complex with Toll-like receptors on these cells initiates transmembrane signaling and cellular activation to secrete cytokines and chemokines (15).Staphylococcal toxic shock syndrome toxin 1 (TSST-1), and the structurally related enterotoxins, are bacterial exotoxins that bind directly to major histocompatibility complex class II molecules on antigen-presenting cells (APC) (4,8,19) and stimulate T cells expressing specific V elements (5, 9). These toxins are called superantigens because of their ability to polyclonally activate large populations of T cells (10). Interaction of SE with APC and T cells also results in hyperproduction of cytokines and chemokines, which is responsible for the pathogenesis of toxic shock (16). These cytokines include tumor necrosis factor alpha (TNF-␣), gamma interferon (IFN-␥), and interleukin 1 (IL-1), proinflammatory mediators with potent immunoenhancing effects (12). In addition, levels of circulating TNF-␣ and IL-1 correlate with the clinical symptoms of sepsis or septic shock (3).In the last decade, numerous clinical trials conducted with antagonists to key mediators such as TNF-␣ (1, 7) or IL-1 (6) have not yielded significant therapeutic benefits for septic patients partly because sepsis is not the result of the release of any one cytokine. Thus, inhibitors that suppress multiple proinflammatory cytokines may be more efficacious for the treatment of septic shock. Recent studies show tricyclodecan-9-yl (D609), a specific inhibitor of phosphatidylcholine-specific phospholipase C (PC-PLC), protects mice from lethal shock induced either by TNF-␣, LPS, or staphylococcal enterotoxin B (SEB) (14). Surprisingly, D609 did not reduce the SEB-induced IL-1, TNF-␣, or IFN-␥ levels in these animals (14). The proposed mechanism of action of D609 is via blockade of the cytotoxic action of TNF-␣. In another study, D609 improved the survival of mice with LPS-induced shock (20), accompanied by a reduction in the levels of IL-1 and IL-6, but not TNF-␣, in serum. In the present study, the modulatory effect of D609 o...