Mechanistic Studies of Polyene Enhancement of Interferon Production by Polyriboinosinic-Polyribocytidylic Acid

Abstract

The production of interferon by polyriboinosinic-polyribocytidylic acid [poly(I) · poly(C)] and poly(I) · poly(C)-diethylaminoethyl-dextran in L929 cells was enhanced from 10 to 100 times by polyene macrolides, including amphotericin B (AmB), AmB methyl ester, nystatin, and filipin. AmB and its water-soluble methyl ester were the most effective; retinol, a nonmacrolide polyene, was ineffective. Interferon induction by Newcastle disease virus was not enhanced by AmB. The kinetics of interferon production were not markedly altered by AmB. Polyenes and poly(I) · poly(C)-diethylaminoethyl-dextran did not need to be present on cells simultaneously to enhance interferon production. Pretreatment with polyenes was as effective as simultaneous addition. Even treatment of washed cells, several hours after removal of poly(I) · poly(C)-diethylaminoethyl-dextran, resulted in enhancement of interferon production. AmB did not appear to form a macromolecular complex with poly(I) · poly(C) in that neither the ultraviolet absorption spectrum nor the melting point of poly(I) · poly(C) was altered by mixing with AmB. Isotopic studies indicated that AmB did not enhance binding of poly(I) · poly(C) to cells. Since the macrolide polyenes have been demonstrated to bind to cell membrane sterols with subsequent alterations in membrane permeability barriers, they may enhance interferon production by increasing cell penetration of poly(I) · poly(C).