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J. Tuo, D. Shen, N. Tuaillon, C. Chan; Endotoxin-induced Uveitis in Cyclooxygenase 2 Deficient Mice . Invest. Ophthalmol. Vis. Sci. 2003;44(13):718.
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Purpose: Cyclooxygenases (COX) are rate-limiting enzymes that initiate the conversion of arachidonic acid to prostanoids, prostacyclins and thromboxanes. There are two isoforms of COX. COX-1 is constitutively expressed in vivo whereas COX-2 is the inducible isoform that is upregulated by proinflammatory agents, triggering many prostanoid-mediated pathological aspects of inflammation. On the other hand, a pathway initiated by lipooxygenase is parallel with COX pathway in arachidonic acid metabolism. The lipooxygenase pathway could be disturbed when COX pathway is blocked. To delineate the role played by COX-2 in acute anterior uveitis, a common ocular inflammation, we studied endotoxin-induced uveitis (EIU) in COX-2 knockout mice. Methods: COX-2 -/-, wild-type matched control (COX-2 +/+, C57Bl/6), and heterozygotic (COX-2 +/-) littermate mice received a single i.p. injection of 100 µg of Salmonella typhimurium lypopolysaccharide (LPS), or co-injection of LPS and IFN-gamma. Mice were euthanized 24 hours after injection. Serum levels of IL-6, IFN-gamma and leukotriene B4 were determined by ELISA. Eyes were collected and analyzed histologically and by RT-PCR for IL-6 and IFN-gamma. Results: EIU was significantly enhanced in COX-2 -/- mice compared to wild-type control mice by histology. EIU score of COX-2 +/- mice was between COX-2 -/- and COX-2 +/+ mice. The number of ocular inflammatory cells was significantly higher in COX-2 -/- mice after LPS injection. IFN-gamma was decreased whereas IL-6 was increased both in the serum and in intraocular transcripts, in COX-2 -/- EIU mice as compared to controls. Leukotriene B4, one of the major metabolites of arachidonic acid by lipooxygenase was greatly increased in COX-2 -/- and COX-2 +/- after LPS injection. EIU was suppressed in COX-2 -/- and COX-2 +/- mice treated with recombinant IFN-gamma. Conclusions: Data indicate that the absence of COX-2 exacerbates EIU. One of the mechanisms could involve the down-regulation of IFN-gamma, a Th1 cytokine that protects against EIU, an ocular inflammation of predominant Th2 response. Alternatively, in the absence of COX-2, the arachidonic acid produced in response to LPS injection could be processed through the lipoxygenase pathway leading to enhanced EIU.
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