Interferon and phorbol esters down-regulate sIgM expression by independent pathways.

Abstract

We studied the effects of recombinant interferon, 12-0-tetradecanoylphorbol-13-acetate (TPA), and phorbol 12, 13 dibutyrate (PDB) on surface immunoglobulin expression by Daudi cells. Incubation of cells with recombinant alpha 2 interferon (IFN-alpha 2) caused a 2.5-fold (60%) decrease in sIgM expression as measured by relative fluorescence index (RFI) using a flow cytometer. This decrease in sIgM expression was independent of inhibitory effects on proliferation and cell cycle progression. TPA or PDB also caused a threefold (67%) decrease in sIgM expression, while enhancing proliferation and cell cycle progression. Coincubation of cells with IFN-alpha 2 and TPA decreased sIgM expression by more than fourfold (greater than 75%), which was greater than the decrease induced by the optimal concentration of either agent alone. Molecular studies demonstrated that the treatment of cells with IFN-alpha 2 or TPA decreased the steady-state levels of mRNA for the heavy chain of IgM (c mu), suggesting that down-regulation of sIgM occurred at a pretranslational level. Activation of the cell membrane sodium/proton antiport did not play an integral role in the IFN-alpha 2 or phorbol-ester-induced pathway of sIgM down-regulation. Whereas IFN-alpha 2 induced an increase in the activity of 2',5'-oligoadenylate (2-5A) synthetase, the addition of TPA to IFN-alpha 2 caused a significant decrease in the activity of this enzyme. Although IFN-alpha 2 and TPA exhibited additive effects on sIgM expression, they had opposing effects on cell proliferation, cell cycle progression, and induction of 2-5A synthetase activity, suggesting that these agents down-regulate sIgM expression through independent pathways.