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Tumor Necrosis Factor-–Induced Apoptosis in Murine Cytomegalovirus Retinitis

¹From the Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta, Georgia; and ²State Key Laboratory of Virology, Institute of Medical Virology, Wuhan University School of Medicine, Wuhan, People’s Republic of China.

PURPOSE. Previous results suggest that apoptosis is involved in the pathogenesis of murine cytomegalovirus (MCMV) retinitis. To explore the mechanism underlying retinal apoptosis in MCMV retinitis, this study was initiated to determine whether the tumor necrosis factor receptor (TNFR)1–TNF pathway is involved in apoptosis during MCMV retinitis.

METHODS. The left eyes of nonimmunosuppressed (non-IS) BALB/c mice, immunosuppressed (IS) BALB/c mice, TNFR1^–/– C57BL/6 mice, and wild-type C57BL/6 mice were inoculated with MCMV k181 by way of the supraciliary route. On postinoculation days 3, 7, and 10, injected eyes of non-IS control and IS experimental mice were removed for RT-PCR for TNF- and TNFR1. Protein expression of TNF-, caspase-8, and caspase-3 was determined by staining frozen sections and performing Western blot analysis and quantitative ELISA. Apoptotic cells were identified by TUNEL labeling.

RESULTS. In IS BALB/c mice, TNF- mRNA and protein were detected in MCMV-infected eyes throughout the infection. Activation of caspase-3 and caspase-8 was observed. Most of the TNF-–expressing cells were MCMV-infected RPE cells or macrophages derived from RPE cells. TNF- was observed in the area of apoptotic retinal cells, and the level of this cytokine corresponded to the extent of the retinal abnormality and to the number of apoptotic cells. In non-IS MCMV–infected BALB/c mice, TNF- was expressed early in the retinas of MCMV-infected eyes, but its expression was decreased thereafter. TNFR1 mRNA was increased in IS and non–IS BALB/c after MCMV infection. More apoptotic cells were observed in the retinas of non-IS MCMV–infected wild-type C57BL/6 mice than in the retinas of non-IS TNFR^–/– mice.

CONCLUSIONS. These results suggest that the TNFR1-TNF pathway is involved in the induction of apoptosis and the exacerbation of retinal abnormality during MCMV retinitis. Furthermore, because TNF- and TNFR1 were present in IS and non-IS mice, TNF-–induced retinal apoptosis during MCMV infection is not T-cell dependent.

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