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-Induced Indoleamine 2,3 Dioxygenase and Inducible Nitric Oxide Synthase in the Replication of Human Cytomegalovirus in Retinal Pigment Epithelial Cells1
*
Unité d’Immunologie Virale, Institut Pasteur, Paris, France; and
Institut National de la Santé et de la Recherche Médicale, U450, Developpement, Vieillissement et Pathologie de la Rétine, Paris, France
An in vitro model of human CMV infection of primary retinal pigment
epithelial (RPE) cells was used to study the effects of cytokines on
CMV replication in these cells, which are targets of CMV infection in
vivo. IFN-
and IFN-ß were potent inhibitors of CMV replication in
RPE cells, while TNF-
, IL-1ß, or TGF-ß2 did not affect viral
replication. Inhibition by IFN-, and to a lesser extent IFN-ß, was
almost completely reversed by addition of L-tryptophan to
the culture medium, strongly implicating the indoleamine 2,3
dioxygenase (IDO) pathway. Polyadenylated IDO mRNA accumulation was
detected as early as 2 h after IFN stimulation. Furthermore, CMV
blocked the production of nitric oxide by the inducible form of nitric
oxide synthase. This inhibition depended on a functional viral genome.
However, exogenous nitric oxide significantly inhibited viral protein
expression in RPE cells. Thus, CMV infection blocks the inducible
nitric oxide synthase pathway activated by IFN- and IL-1ß, but
cannot counteract the IFN-induced IDO pathway, which ultimately
controls its replication in primary human RPE
cells.
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