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Human Cytomegalovirus Circumvents NF-B Dependence in Retinal Pigment Epithelial Cells¹

Jindrich Cinatl, Jr^2,*, Stefan Margraf^*, Jens-Uwe Vogel^*,, Martin Scholz, Jaroslav Cinatl^, and Hans Wilhelm Doerr^*

^* Zentrum der Hygiene, Institut für Medizinische Virologie, Zentrum für Kinderheilkunde und Jugendmedizin, Abteilung Pädiadrische Hämatologie und Onkologie, and Klinikum für Thorax-, Herz- und thorakale Gefächirurgie, Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany; and KlinLab, Prague, Czech Republic

The human CMV (HCMV) is a persistent virus that may cause severe inflammatory responses especially in immunocompromised hosts. In different cell types, HCMV infection leads to the activation of the pleiotropic transcription factor, NF-B, which triggers virus replication but also propagates cell-mediated inflammatory mechanisms that largely depend on PG synthesis. We investigated the interactions of HCMV and the NF-B-dependent PG synthesis pathway in cultures of retinal pigment epithelial (RPE) cells that are known to be infected in HCMV retinitis patients. Unlike in other cell types, HCMV increased neither NF-B activity nor p65 and p105/50 mRNA levels in RPE cells. Both TNF- and phorbol ester 12,0-tetradecanoylphorbol 13-acetate (TPA) enhanced NF-B activity but only TPA increased HCMV replication. Cyclooxygenase-2 expression and PGE₂ release was increased by TPA and TNF- but not by HCMV infection. Stimulatory activity of TPA on HCMV replication was suppressed by protein kinase C inhibitors and inhibitors of p42/44 and p38 mitogen-activated protein kinases but not by NF-B inhibitors. In conclusion, HCMV circumvents the NF-B route in favor of the protein kinase C-dependent mitogen-activated protein kinase pathway in RPE cells. This virus/host cell interaction might be a mechanism that promotes HCMV persistence in immune-privileged organs such as the eye.

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