RESUMO
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.
Assuntos
Antígenos CD/fisiologia , Interleucinas/fisiologia , Glicoproteínas de Membrana/fisiologia , Receptores de Citocinas/fisiologia , Transdução de Sinais/imunologia , Animais , Anticorpos Bloqueadores/farmacologia , Anticorpos Monoclonais/farmacologia , Antígenos CD/biossíntese , Antígenos CD/imunologia , Antígenos CD/metabolismo , Comunicação Autócrina/imunologia , Linhagem Celular Tumoral , Células Cultivadas , Receptor gp130 de Citocina , Citocinas/biossíntese , Citocinas/genética , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/metabolismo , Regulação da Expressão Gênica/imunologia , Humanos , Mediadores da Inflamação/metabolismo , Interleucinas/antagonistas & inibidores , Mastócitos/imunologia , Mastócitos/metabolismo , Glicoproteínas de Membrana/biossíntese , Glicoproteínas de Membrana/imunologia , Glicoproteínas de Membrana/metabolismo , Camundongos , Monócitos/imunologia , Monócitos/metabolismo , Células NIH 3T3 , Fosforilação , RNA Mensageiro/biossíntese , Receptores de Citocinas/biossíntese , Receptores de Interleucina , Fator de Transcrição STAT1 , Fator de Transcrição STAT3 , Transativadores/antagonistas & inibidores , Transativadores/metabolismo , Transcrição Gênica/imunologia , Ativação Transcricional , Tirosina/metabolismoRESUMO
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.
