IL-4 enhances IFN-λ1 (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: IFN-lambda 1 (interleukin-29 [IL-29]), IFN-lambda 2 (IL-28A), and IFN-lambda 3 (IL-28B), each of which signals through the same receptor complex. Plasmacytoid dendritic cells (pDCs) are major IFN-lambda producers among peripheral lymphocytes. Recently, it has been shown that IFN-lambda 1 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 IFN-lambda production. IL-4 treatment during stimulation of human peripheral lymphocytes significantly elevated IFN-lambda 1 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 IFN-lambda 1 output. Thus, our experiments revealed a novel mechanism for regulation of both IFN-lambda 1 production and pDC function, and suggests an expanded immunomodulatory role for Th2-associated cytokines. (Blood. 2010; 115(21): 4185-4190)