Abstract 1132: Antinflammatory role of macrophage Cyclooxygenase 2 derived prostaglandins in vivo
Nonsteroidal anti-inflammatory drugs, including those selective for cyclooxygenase (COX) - 2 relieve pain and inflammation. Thus, suppression of COX-2 derived proinflammatory products is a cardinal feature of NSAID efficacy. The use of conventional COX-2 knockout mice to explore this biology is constrained by the multiple roles of COX-2 in development and early postnatal life. To circumvent these limitations we generated mice with tissue-specific COX-2 deletion in macrophages (COX-2Mac−/−) confirmed by absence of LPS inducible mRNA and protein and maximal suppression of evoked formation of thromboxane (Tx), prostacyclin (PGI2) and prostaglandin E2 by macrophages ex vivo. Deletion of macrophage COX-2 depressed LPS evoked systemic generation of these prostanoids by 35 – 40%. Surprisingly, deletion of macrophage COX-2 amplified the hypotensive response and blunted the thermal response to systemic LPS and shortened survival. Exposure of peritoneal macrophages to LPS ex vivo revealed a pro-inflammatory cytokine profile in the COX-2Mac−/− cells; higher levels of tumor necrosis factor - α and interleukin 6, but a reduction in interleukin 10. Products of COX-2 in macrophages can subserve both pro- and antinflammatory roles in vivo. Cell selective deletion of COX-2 permits delineation of cellular contributions to indices of systemic prostanoid biosynthesis and elucidation of prostanoid biology in complex multicellular disease processes, such as pertain in atherosclerosis.