Role of Thromboxane A 2 in the Induction of Apoptosis of Immature Thymocytes by Lipopolysaccharide

Abstract

ABSTRACT 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 thromboxane-prostanoid (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 μg 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 TP-deficient 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.