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Role of Thromboxane A₂ in the Induction of Apoptosis of Immature Thymocytes by Lipopolysaccharide

Paulo N. Rocha,^1, Troy J. Plumb,¹ Lisa A. Robinson,¹ Robert Spurney,¹ David Pisetsky,² Beverly H. Koller,³ and Thomas M. Coffman^1*

Division of Nephrology, Duke University, and Durham VA Medical Centers, Durham, North Carolina,¹ Division of Immunology, Duke University, and Durham VA Medical Centers, Durham, North Carolina,² Department of Medicine, the University of North Carolina, Chapel Hill, North Carolina³

Received 17 March 2005/ Returned for modification 13 April 2005/ Accepted 4 May 2005

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 A₂ (TXA₂) causes apoptosis of these cells, we tested whether enhanced generation of TXA₂ plays a role in LPS-induced thymocyte apoptosis. Mice injected with 50 µg of LPS intraperitoneally displayed a marked increase in generation of TXA₂ and prostaglandin E₂ 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 TXA₂ 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.

Present address: Hospital Universitario Professor Edgard Santos, Laboratorio de Imunologia, 5^o andar, Rua João das Botas s/n, Canela, Salvador-BA, 40110-160, Brazil.