Regulation of human interferon production stimulated with poly(I) · Poly(C): Correlation between shutoff and hyporesponsiveness to reinduction

Abstract

The exposure of FS-4 cells to polyinosinate-polycytidylate [poly(I) · poly(C), 2 μg/ml] for 1 hr resulted in rapid interferon production which peaked in 3–4 hr and was rapidly shut off thereafter, declining to low or undetectable levels by 6 hr. Reexposure of cells to 50 μg/ml of poly(I) · poly(C) at 2, 3, 4, or 5 hr after the first induction did not prevent the s shut off of interferon production due to the first induction. However, the restimulated cultures underwent a second round of interferon production peaking at 8–10 hr. The appearance of the second peak could be inhibited with actinomycin D, if the drug was added 3 hr after reexposure to poly(I) · poly(C), i.e., before the actual onset of the second round of interferon production. The second interferon peak resembled the peak seen a after the first induction in that it also showed a rather steep rise and rapid shutoff. The shutoff of the second peak could be prevented by treatment with actinomycin D at 9 hr (5 hr after the second stimulation). A second interferon peak at 9 hr was also seen following a single 1-hr exposure to a high concentration (50 μg/ml) of poly(I) · poly(C). It is suggested that a rapidly turning over repressor system is induced coordinately with interferon. This repressor system causes irreversible inactivation of interferon mRNA and is likely to be responsible for the shutoff of interferon production as well as the phenomenon of hyporesponsiveness to repeated interferon induction.