Arch Virol (1989) 109:25-34 Archives Virology © by Springer-Verlag 1989 Differential modulating effects of retinoic acid on interferon antiviral activity Chi-Kuan Ho 1, 2, Bor-Rung Ou 1, Ching-Yun Wang 1, Hour-Young Chen 3, and Tsuguo Kuwata 4 1 Department of Medical Research, Veterans General Hospital, Taipei, 2Institute of Microbiology and Immunology, Yang Ming Medical College, Taipei, and 3Institute of Preventive Medicine, Taipei, Taiwan, Republic of China 4Department of Microbiology, School of Medicine, Chiba University, Chiba, Japan Accepted September 8, 1989 Summary. The effect of retinoic acid (RA) on the antiviral activity ofinterferons (IFNs) a and [3 in the U937 and WISH cells was examined to ascertain whether or not RA could reduce the effectiveness of IFN-induced resistance to viral infection. Our results indicate that in the U937 cells, RA (0.1-1.0 IzM) had neither enhancing nor suppressive effect on the antiviral activity of IFN-a or ]3 against the Semliki Forest virus (SFV). However, in the WISH cells, RA had different effects on IFNs a and [3. Thus, while RA (0.1-50 ~tM) invariably suppressed the activity of IFN-a, it enhanced the action of IFN-[3 at low dose (0.1-1.0 ~tM) but became suppressive at higher concentrations (~> 10 ~tM). Fur- thermore, higher antiviral activity was consistently obtained when RA (0.1- 10 I~M) was added prior to either IFN-a or IFN-13 comparing to cultures with IFN alone. In addition, direct correlation between antiviral activity and the amplitude of 2-5 oligoadenylate (A) synthetase activity was not observed. These results suggest that modulation of IFN antiviral activity by RA varies with different systems and is dependent on the sequence of treatment. Introduction Interferons (IFNs) and retinoids share a number of functional properties [24, 34] including the ability to suppress virus replication [28, 33] and to induce 2-5A synthetase activity [7]. However, it has been repeatedly shown that retinoic acid (RA) can antagonize the antiviral [4] and immunoregulatory [1, 29] activities of IFNs. Furthermore, retinoids can suppress the induction of IFN in vitro and decrease the level of serum IFN in vivo [5, 11]. The fact that RA can antagonize the induction and functions of IFNs may make one cautious