Abstract
Human cytomegalovirus (HCMV) infection can be fatal to immunocompromised individuals. We have previously reported that gamma interferon and tumor necrosis factor alpha (TNF-alpha) synergistically inhibit HCMV replication in vitro. Ceramides have been described as second messengers induced by TNF-alpha. To investigate the mechanisms involved in the inhibition of HCMV by TNF-alpha, in the present study we have analyzed ceramide production by U373 MG astrocytoma cells and the effects of TNF-alpha versus ceramides on HCMV replication. Our results show that U373 MG cells did not produce ceramides upon incubation with TNF-alpha. Moreover, long-chain ceramides induced by treatment with exogenous bacterial sphingomyelinase inhibited HCMV replication in synergy with TNF-alpha. Surprisingly, short-chain permeant C6-ceramide increased viral replication. Our results show that the anti-HCMV activity of TNF-alpha is independent of ceramides. In addition, our results suggest that TNF-alpha and endogenous long-chain ceramides use separate pathways of cell signalling to inhibit HCMV replication, while permeant C6-ceramide appears to activate a third pathway leading to an opposite effect.
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