Lack of TNF-?± Promotes Caspase-3a??Independent Apoptosis during Murine Cytomegalovirus Retinitis

摘要

Purpose.: Both caspase-dependent and caspase-independent apoptosis contribute to retinal damage during murine cytomegalovirus (MCMV) retinitis, and TNF-?± is among the inducers of apoptosis. The aim of this study was to determine the contribution of TNF-?± by studying virus replication and apoptosis in immunosuppressed (IS) TNF-?±a??/a?? mice. Methods.: IS TNF-?±a??/a?? mice or wild-type mice were inoculated with MCMV by the supraciliary route. Injected eyes were examined by plaque assay, electron microscopy, Western blot analysis (caspase-3, caspase-8, caspase-12, Bid, NF-?oB, cFlip, XIAP), staining for MCMV early antigen, and TUNEL assay. Results.: Although the titer of MCMV was similar in both groups, significantly more apoptotic cells were observed in the retinas of IS TNF-?±a??/a?? mice than in those of wild-type mice. The level of active caspase-3 was similar in both groups; however, more activated proteins for genes involved in the mitochondrial pathway (cleaved caspase-8, tBid) and endoplasmic reticulum (ER) stress (cleaved caspase-12) and, though less active, NF-?oB subunits and antiapoptotic proteins (XIAP and cFlip) were detected in the TNF-?±a??/a?? eyes compared with wild-type mice. Conclusions.: Although TNF-?± is an inducer of apoptosis, the results of this study suggest that TNF-?± is also antiapoptotic by the following mechanism: TNF-?± activation of NF-?oB promotes the production of the antiapoptosis genes, c-flip or XIAP, which, in turn, inhibit the activation of caspase-8 and the mitochondrial pathway or the activation of caspase-12 and ER stress.