RESUMEN
BACKGROUND: Patients with rheumatoid arthritis (RA) have a systemic Th1 defect associated with inflammation. OBJECTIVE: To examine the hypothesis that interleukin 17 (IL-17) contributes to this defect. METHODS: IL-17 effects on Th1 markers were examined on T-bet and interferon gamma (IFNgamma) expression in peripheral blood mononuclear cells (PBMCs) from patients with RA or healthy controls (HC). Receptor specificities were determined by analysis of the Th1-specific IL-12 receptor beta2 (IL-12Rbeta2), Th17-specific IL-23R and the common IL-12Rbeta1 chain expression. Effects of IL-17 or IFNgamma on IL-6, IL-1, IL-8, matrix metalloproteinase-8 (MMP-8) were measured by real-time RT-PCR in RA synovial cells. RESULTS: RA PBMCs were less responsive to IL-12-induced IFNgamma than HC PBMCs. IL-12 hyporesponsiveness was increased by IL-17 treatment associated with a selective reduction in IL-12Rbeta2, but not IL-23R, IL-12Rbeta1 or T-bet, which was reversed with IL-17R inhibition. IL-17 inhibited IL-12Rbeta2 expression in developing Th1 cells. In RA synovial cells, IL-17 induced IL-6, IL-1, IL-8 and MMP-8, whereas IFNgamma had minimal or inhibitory effects. CONCLUSION: In RA, IL-12 hyporesponsiveness is associated with IL-17R-mediated downregulation of IL-12Rbeta2 expression. IL-17 may reinforce Th17 lineage commitment and proinflammatory and destructive effects through Th1 inhibition and positive feedback effects in RA synovial cells. Anti-inflammatory effects of IL-17/IL-17R antagonism may include the restoration of protective Th1 responses.
Asunto(s)
Artritis Reumatoide/inmunología , Interleucina-17/inmunología , Receptores de Interleucina-12/antagonistas & inhibidores , Células TH1/inmunología , Adulto , Comunicación Celular/inmunología , Diferenciación Celular/inmunología , Células Cultivadas , Regulación hacia Abajo/inmunología , Femenino , Humanos , Interferón gamma/biosíntesis , Interferón gamma/genética , Masculino , Persona de Mediana Edad , Monocitos/inmunología , ARN Mensajero/genética , Receptores de Interleucina-12/inmunología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Membrana Sinovial/inmunología , Proteínas de Dominio T Box/biosíntesisRESUMEN
Th17 cells are critical in adaptive immunity and autoimmune disease. The polarized development of Th17, Th1 and Th2 cells is dependent on counterregulatory effects on each other. Whereas IFN-gamma inhibits Th17 development, the effect of IL-17 in human Th1 development is not known. We report a novel negative regulatory role of IL-17 on IL-12R beta 2 expression associated with reduced IL-12 responsiveness. IL-17 decreased IL-12-induced IFN-gamma expression in PBMC and developing Th1 cells, associated with a selective reduction in IL-12R beta 2, and not IL-23R, IL-12R beta 1 or T-bet. Counterregulatory effects of human Th17 on Th1 lineage cytokines may contribute to lineage divergence. In autoimmune disease, IL-17 may reinforce its own developmental programme by reducing IL-12 responsiveness, thus limiting inhibitory effects of IFN-gamma on Th17 development.