IMMUNOBIOLOGY IL-4 enhances IFN- 1 (IL-29) production by plasmacytoid DCs via monocyte secretion of IL-1Ra

The type-III interferon (IFN) family is composed of 3 molecules in humans: IFN1 (interleukin-29 [IL-29]), IFN2 (IL-28A), and IFN3 (IL-28B), each of which signals through the same receptor complex. Plasmacytoid dendritic cells (pDCs) are major IFNproducers among peripheral lymphocytes. Recently, it has been shown that IFN1 exerts a powerful inhibitory effect over the T-helper 2 (Th2) response by antagonizing the effect of IL-4 on CD4 T cells and inhibiting the production of Th2-associated cytokines. Here, we asked whether Th2 cytokines exert reciprocal control over IFNproduction. IL-4 treatment during stimulation of human peripheral lymphocytes significantly elevated IFN1 transcription and secretion. However, pDCs were not directly responsive to IL-4. Using depletion and reconstitution experiments, we showed that IL-4– responsive monocytes are an intermediary cell, responding to IL-4 by elevating their secretion of IL-1 receptor antagonist (IL-Ra); this IL-1Ra acts on pDCs to elevate their IFN1 output. Thus, our experiments revealed a novel mechanism for regulation of both IFN1 production and pDC function, and suggests an expanded immunomodulatory role for Th2-associated cytokines. (Blood. 2010; 115(21):4185-4190)