Lipopolysaccharide (LPS) causes apoptotic deletion of CD4؉ CD8 ؉ thymocytes, a phenomenon that has been linked to immune dysfunction and poor survival during sepsis. Given the abundance of thromboxaneprostanoid (TP) receptors in CD4 ؉ CD8 ؉ thymocytes and in vitro evidence that thromboxane A 2 (TXA 2 ) causes apoptosis of these cells, we tested whether enhanced generation of TXA 2 plays a role in LPS-induced thymocyte apoptosis. Mice injected with 50 g of LPS intraperitoneally displayed a marked increase in generation of TXA 2 and prostaglandin E 2 in the thymus as well as apoptotic deletion of CD4 ؉ CD8 ؉ thymocytes. Administration of indomethacin or rofecoxib inhibited prostanoid synthesis but did not affect thymocyte death. In contrast, thymocyte apoptosis in response to LPS was significantly attenuated in TPdeficient mice. These studies indicate that TXA 2 mediates a portion of apoptotic thymocyte death caused by LPS. The absence of an effect of global inhibition of prostanoid synthesis suggests a complex role for prostanoids in this model.Bacterial sepsis is associated with apoptotic cell death in a variety of organs and tissues, including the thymus (16,19,42). The LPS component of gram-negative bacteria appears to mediate most of these effects, since injection of LPS into mice is followed by a dramatic reduction in thymocyte numbers, simulating the situation during sepsis. LPS does not cause thymocyte apoptosis directly, as addition of LPS to in vitro cultures of thymocytes does not result in apoptosis of these cells (43). This result is not surprising, as thymocytes are not known to express the main LPS receptor, TLR4. Therefore, thymocyte apoptosis following LPS injection in vivo is likely mediated by soluble factors produced by TLR4-expressing cells of the innate immune system. The identification of such mediators could have implications for therapy, since recent evidence suggests that lymphocyte apoptosis during sepsis is deleterious because it might impair immune responses and contribute to mortality (20).Prostanoids are produced by cells of the innate immune system exposed to LPS (27). TXA 2 is a prostanoid mediator derived by the sequential metabolism of cell membrane phospholipids by phospholipases, COX, and thromboxane synthase. During inflammatory states, this metabolic pathway is induced, resulting in enhanced TXA 2 production (39). TXA 2 has long been known for its vasoconstrictive and procoagulant properties, but a recent study revealed a novel and important role for this molecule in cell-mediated immunity (38). In addition, several lines of investigation point toward TXA 2 as a potential mediator of thymocyte apoptosis. First, Nusing et al. showed that the activity of TXA 2 synthase in dendritic cells of the thymic stroma is as high as it is in platelets (26). Second, Namba and coworkers demonstrated that the thymus is the organ with the highest concentration of TP receptors (24). In the thymus, immature CD4 ϩ CD8 ϩ thymocytes have the highest concentrations of TP receptors among cells; when...