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Multiorgan Transplant Program and Departments of
*
Medicine,
Surgery, and
Pathology, The Toronto Hospital and The University of Toronto, Toronto, Canada M5G 2C4
Ribavirin, a synthetic guanosine analogue, possesses a broad
spectrum of activity against DNA and RNA viruses. It has been
previously shown to attenuate the course of fulminant hepatitis in mice
produced by murine hepatitis virus strain 3. We therefore studied the
effects of ribavirin on murine hepatitis virus strain 3 replication,
macrophage production of proinflammatory mediators including TNF, IL-1,
and the procoagulant activity (PCA), fgl2 prothrombinase; and Th1/Th2
cytokine production. Although ribavirin had inhibitory effects on viral
replication (<1 log), even at high concentrations complete eradication
of the virus was not seen. In contrast, at physiologic concentrations
(up to 500 µg/ml), ribavirin markedly reduced viral-induced
parameters of macrophage activation. With ribavirin treatment, the
concentrations of PCA, TNF-
and IL-1ß all decreased to basal
concentrations: PCA from 941 ± 80 to 34 ± 11
mU/106 cells; TNF- from 10.73 ± 2.15 to
2.74 ± 0.93 ng/ml; and IL-1ß from 155.91 ± 22.62 to
5.74 ± 0.70 pg/ml. The inhibitory effects of ribavirin were at
the level of gene transcription as evidenced by Northern analysis. Both
in vitro and in vivo, ribavirin inhibited the production of IL-4 by Th2
cells, whereas it did not diminish the production of IFN-
in Th1
cells. In contrast, ribavirin had no inhibitory effect on TNF- and
IL-1ß production in LPS-stimulated macrophages. These results suggest
that the beneficial effects of ribavirin are mediated by inhibition of
induction of macrophage proinflammatory cytokines and Th2 cytokines
while preserving Th1 cytokines.
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