Production of Interferon-α Induced by dsRNA in Human Peripheral Blood Mononuclear Cell Cultures: Role of Priming by dsRNA-Induced Interferons-γ and -β

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Abstract
Poly(I):poly(C) (rIn.rCn), mismatched poly(I):poly(C) [rIn.r(C12U)n], and poly(I): poly(C) poly-lysine carboxymethylcellulose [poly(ICLC)] were studied for their capacity to induce interferon-α (IFN-α) in human peripheral blood mononuclear cell (MNC) cultures and in their subpopulations. In MNC, poly(I):poly(C) and mismatched poly(I): poly(C) induced IFN-α in a dose-dependent manner, whereas poly(ICLC) was unable to do so in concentrations that ranged from 1 to 160 μg/ml. In contrast, all three molecules were incapable of inducing IFN-α when added into either purified monocyte or lymphocyte cultures. The capacity of poly(I):poly(C) to induce IFN-α was reestablished only in monocyte cultures when, prior to the stimulation, the cells were exposed for at least 2 h to supernatants from poly(I):poly(C)-stimulated lymphocyte cultures. IFN-β and IFN-γ were found in those supernatants and the ability of each dsRNA to induce IFN-α correlated with its ability to induce IFN-γ. Further studies using recombinant human IFN-γ and IFN-β and their specific antibodies corroborated an important role of these molecules for the induction of IFN-α with dsRNA. Because each IFN type is produced by different cells, our studies show that complex cell-to-cell interactions via other IFNs have to take place in peripheral blood mononuclear cells (MNC) cultures before IFN-α can be induced by dsRNA.