ABSTRACT
The recently discovered cytokine IL-27 belongs to the IL-6/IL-12 family of cytokines and induced proliferation of naive CD4(+) T cells and the generation of a Th1-type adaptive immune response. Although binding of IL-27 to the cytokine receptor WSX-1 was demonstrated, this interaction proved insufficient to mediate cellular effects. Hence, IL-27 was believed to form a heteromeric signaling receptor complex with WSX-1 and another, yet to be identified, cytokine receptor subunit. In this study, we describe that WSX-1 together with gp130 constitutes a functional signal-transducing receptor for IL-27. We show that neither of the two subunits itself is sufficient to mediate IL-27-induced signal transduction, but that the combination of both is required for this event. Expression analysis of WSX-1 and gp130 by quantitative PCR suggests that IL-27 might have a variety of cellular targets besides naive CD4(+) T cells: we demonstrate gene induction of a subset of inflammatory cytokines in primary human mast cells and monocytes in response to IL-27 stimulation. Thus, IL-27 not only contributes to the development of an adaptive immune response through its action on CD4(+) T cells, it also directly acts on cells of the innate immune system.
Subject(s)
Antigens, CD/physiology , Interleukins/physiology , Membrane Glycoproteins/physiology , Receptors, Cytokine/physiology , Signal Transduction/immunology , Animals , Antibodies, Blocking/pharmacology , Antibodies, Monoclonal/pharmacology , Antigens, CD/biosynthesis , Antigens, CD/immunology , Antigens, CD/metabolism , Autocrine Communication/immunology , Cell Line, Tumor , Cells, Cultured , Cytokine Receptor gp130 , Cytokines/biosynthesis , Cytokines/genetics , DNA-Binding Proteins/antagonists & inhibitors , DNA-Binding Proteins/metabolism , Gene Expression Regulation/immunology , Humans , Inflammation Mediators/metabolism , Interleukins/antagonists & inhibitors , Mast Cells/immunology , Mast Cells/metabolism , Membrane Glycoproteins/biosynthesis , Membrane Glycoproteins/immunology , Membrane Glycoproteins/metabolism , Mice , Monocytes/immunology , Monocytes/metabolism , NIH 3T3 Cells , Phosphorylation , RNA, Messenger/biosynthesis , Receptors, Cytokine/biosynthesis , Receptors, Interleukin , STAT1 Transcription Factor , STAT3 Transcription Factor , Trans-Activators/antagonists & inhibitors , Trans-Activators/metabolism , Transcription, Genetic/immunology , Transcriptional Activation , Tyrosine/metabolismABSTRACT
An efficient Th1-driven adaptive immune response requires activation of the T cell receptor and secretion of the T cell stimulatory cytokine IL-12 by activated antigen-presenting cells. IL-12 triggers Th1 polarization of naive CD4(+) T cells and secretion of IFN-gamma. We describe a new heterodimeric cytokine termed IL-27 that consists of EBI3, an IL-12p40-related protein, and p28, a newly discovered IL-12p35-related polypeptide. IL-27 is an early product of activated antigen-presenting cells and drives rapid clonal expansion of naive but not memory CD4(+) T cells. It also strongly synergizes with IL-12 to trigger IFN-gamma production of naive CD4(+) T cells. IL-27 mediates its biologic effects through the orphan cytokine receptor WSX-1/TCCR.
