IL-4 enhances IFN-lambda1 (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-lambda1 (interleukin-29 [IL-29]), IFN-lambda2 (IL-28A), and IFN-lambda3 (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-lambda1 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-lambda1 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-lambda1 output. Thus, our experiments revealed a novel mechanism for regulation of both IFN-lambda1 production and pDC function, and suggests an expanded immunomodulatory role for Th2-associated cytokines.
Megjugorac
Nicholas J
NJ
Humigen LLC, The Institute for Genetic Immunology, Hamilton, NJ 08690, USA.
Gallagher
Grant E
GE
Gallagher
Grant
G
D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D018259:Herpesvirus 1, Human / Q000276:immunology; D006801:Humans; D066298:In Vitro Techniques; D007372:Interferons; D053590:Interleukin 1 Receptor Antagonist Protein / Q000096:biosynthesis*; D015847:Interleukin-4 / Q000494:pharmacology*; D007378:Interleukins / Q000096:biosynthesis* / Q000235:genetics; D018448:Models, Immunological; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D000095022:Interferon Lambda
D007372:Interferons; D053590:Interleukin 1 Receptor Antagonist Protein; D015847:Interleukin-4; D007378:Interleukins; D011994:Recombinant Proteins; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C508598:IL4 protein, human