Abstract 922 Cytokines in Disease and Therapy Poster Symposium, Monday, 5/3

Objective: The role of inflammatory mediators in the pathogenesis of RSV disease is not well understood. In vitro experiments and clinical studies have demonstrated that RSV can induce the production of different pro-inflammatory cytokines and chemokines. Ribavirin is a broad-spectrum antiviral agent with significant in vitro and in vitro activity against RSV. Recent studies with murine hepatitis virus 3 (J Immunol 1998: 160-3487) suggest that ribavirin may have also an immunomodulatory effect on cytokine production. The present study was designed to determine the effect of ribavirin on the production of pro-inflammatory cytokines induced by RSV in pulmonary epithelial cells.

Methods: Monolayers of lung type II alveolar epithelial cells (A549) were infected with RSV Long strain and treated with different concentrations of Ribavirin. Culture supernatants were collected at 4, 24, 48 and 72 hours. Concentrations of IL-6, MIP-1α and RANTES were measured by ELISA and RSV titers were determined by standard plaque assays in HEp-2 cells.

Results: RSV infection of A549 cells induced a significant production of IL-6 (median: 11,286 pg/ml), MIP-1α (2,593 pg/ml) and RANTES (64,472 pg/ml) after 48 hours of incubation. Ribavirin significantly suppressed the production of IL-6, MIP-1α and RANTES (p ≤ 0.001 at 48 hours for all three cytokines) in a dose-dependent fashion. The reduction of cytokines produced was significant, even when small concentrations of ribavirin were used. At 48 hours, ribavirin (10 µ/ml) reduced RANTES concentrations by 81%, MIP-1α by 97% and IL-6 by 87%. RSV titers were reduced in a dose-dependent manner as well.

Conclusions: Ribavirin significantly reduces the production of pro-inflammatory cytokines induced by RSV. Further studies will be necessary to better define this effect and to determine whether this is a consequence of its antiviral activity against RSV or it is an independent immunomodulatory effect. This may have important implications for designing new combined therapeutic strategies for RSV disease.

Supported in part by an educational grant from ICN Pharmaceuticals Inc.