RIBAVIRIN INHIBITS VIRAL-INDUCED MACROPHAGE PRODUCTION OF TNF, IL-1, THE PROCOAGULANT FGL2 PROTHROMBINASE AND PRESERVES TH1 CYTOKINE PRODUCTION BUT INHIBITS TH2 CYTOKINE RESPONSE

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 mur ine hepatitis virus strain 3, We therefore studied the effects of riba virin on murine hepatitis virus strain 3 replication, macrophage produ ction of proinflammatory mediators including TNF, IL-1, and the procoa gulant activity (PCA), fgl2 prothrombinase; and Th1/Th2 cytokine produ ction, Although ribavirin had inhibitory effects on viral replication (<1 log), even at high concentrations complete eradication of the viru s was not seen, In contrast, at physiologic concentrations (up to 500 mu g/ml), ribavirin markedly reduced viral-induced parameters of macro phage activation, With ribavirin treatment, the concentrations of PCA, TNF-alpha and IL-1 beta all decreased to basal concentrations: PCA fr om 941 +/- 80 to 34 +/- 11 mU/10(6) cells; TNF-alpha from 10.73 +/- 2. 15 to 2.74 +/- 0.93 ng/ml; and IL-1 beta 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 vitr o and in vivo, ribavirin inhibited the production of IL-4 by Th2 cells , whereas it did not diminish the production of IFN-gamma in Th1 cells , In contrast, ribavirin had no inhibitory effect on TNF-alpha and IL- 1 beta production in LPS-stimulated macrophages, These results suggest that the beneficial effects of ribavirin are mediated by inhibition o f induction of macrophage proinflammatory cytokines and Th2 cytokines while preserving Th1 cytokines.