Thrombin induces Sp1-mediated antiviral effects in cytomegalovirus-infected human retinal pigment epithelial cells.
Human cytomegalovirus (HCMV) retinitis causing retinal detachment and destruction of the blood-retina barrier is closely related to retinal hemorrhage/coagulation. However, the effects of procoagulants on HCMV (re)activation in retinal cells have not been investigated yet. Therefore, we studied whether thrombin modulates the expression of HCMV immediate early (IE) and late (L) genes in cultured human retinal pigment epithelial cells (RPE). Thrombin specifically stimulated the protease-activated receptor-1 (PAR-1) on RPE and, surprisingly, inhibited basal and 12,0-tetradecanoylphorbol 13-acetate-stimulated HCMV IE gene expression in infected RPE. On the other hand, HCMV strongly induced Sp1 DNA binding activity, which was prevented by thrombin/PAR1-mediated Sp1 hyperphosphorylation. Our data suggest that thrombin/PAR-1 may inhibit Sp1-dependent HCMV replication, which might be an important regulatory mechanism for HCMV persistence and replication in RPE.
D000998:Antiviral Agents; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000502:physiology*; D015967:Gene Expression Regulation, Viral; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis; D010857:Pigment Epithelium of Eye / Q000821:virology*; D044463:Receptor, PAR-1 / Q000378:metabolism; D015398:Signal Transduction; D016329:Sp1 Transcription Factor / Q000378:metabolism; D013917:Thrombin / Q000502:physiology*; D015534:Trans-Activators / Q000096:biosynthesis; D014764:Viral Proteins / Q000096:biosynthesis; D014775:Virus Activation
D000998:Antiviral Agents; C088645:IE1 protein, cytomegalovirus; C069186:IE2 protein, Cytomegalovirus; D017874:Immediate-Early Proteins; D044463:Receptor, PAR-1; D016329:Sp1 Transcription Factor; D015534:Trans-Activators; D014764:Viral Proteins; D013917:Thrombin