title: Distinct pathways for tumor necrosis factor alpha and ceramides in human cytomegalovirus infection.
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.
authors.affiliation: INSERM U.395, Toulouse, France.
authors.forename: J
authors.initials: J
authors.lastname: Allan-Yorke
authors.forename: M
authors.initials: M
authors.lastname: Record
authors.forename: C
authors.initials: C
authors.lastname: de Préval
authors.forename: C
authors.initials: C
authors.lastname: Davrinche
authors.forename: J L
authors.initials: JL
authors.lastname: Davignon
mesh_terms: D000998:Antiviral Agents / Q000378:metabolism* / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002518:Ceramides / Q000378:metabolism* / Q000494:pharmacology; D003587:Cytomegalovirus / Q000187:drug effects*; D006801:Humans; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; D002518:Ceramides; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C101954:N-caproylsphingosine; D017871:Calcium-Calmodulin-Dependent Protein Kinases