RESUMO
Interleukin-17 (IL-17) is a T-cell-derived cytokine that promotes inflammatory pathology in autoimmune diseases. Blocking IL-17A interactions with its endogenous IL-17 receptor (IL-17RA) can constitute an important target for therapeutic intervention. Here, we utilized a directed evolution approach to generate soluble IL-17RA mutants that exhibit increased IL-17A binding affinity and thermostability, relative to the wild-type. Human fibroblast cell-based assay and in vivo analysis in mice indicated that two improved IL-17RA mutants efficiently inhibit the secretion of IL-17A-induced proinflammatory cytokines. Analysis of one of these mutants in a psoriasis mouse model showed its efficacy in promoting the recovery of psoriasis plaques. This mutant can be used as a promising drug candidate for the treatment of psoriasis and may be a therapeutic agent for various other autoimmune diseases.
Assuntos
Evolução Molecular Direcionada , Interleucina-17/metabolismo , Psoríase/tratamento farmacológico , Receptores de Interleucina-17/uso terapêutico , Animais , Modelos Animais de Doenças , Humanos , Cinética , Camundongos , Mutação , Ligação Proteica , Estabilidade Proteica , Receptores de Interleucina-17/genética , Receptores de Interleucina-17/metabolismo , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/genética , Proteínas Recombinantes/uso terapêuticoRESUMO
IL-17 is the defining cytokine of a newly-described "Th17" population that plays critical roles in mediating inflammation and autoimmunity. The IL-17/IL-17 receptor superfamily is the most recent class of cytokines and receptors to be described, and until recently very little was known about its function or molecular biology. However, in the last year important new insights into the composition and dynamics of the receptor complex and mechanisms of downstream signal transduction have been made, which will be reviewed here.
Assuntos
Receptores de Interleucina-17/fisiologia , Transdução de Sinais/fisiologia , Animais , Anticorpos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Remodelação Óssea/fisiologia , Proteínas Estimuladoras de Ligação a CCAAT/fisiologia , Citocinas/imunologia , Humanos , Mediadores da Inflamação/fisiologia , Interleucina-6/fisiologia , NF-kappa B/fisiologia , Estrutura Terciária de Proteína , Receptores de Interleucina-17/uso terapêutico , Relação Estrutura-Atividade , Linfócitos T Auxiliares-Indutores/fisiologia , Fatores de Transcrição/fisiologiaRESUMO
The proinflammatory cytokines IL-17A and IL-17F have a high degree of sequence similarity and share many biological properties. Both have been implicated as factors contributing to the progression of inflammatory and autoimmune diseases. Moreover, reagents that neutralize IL-17A significantly ameliorate disease severity in several mouse models of human disease. IL-17A mediates its effects through interaction with its cognate receptor, the IL-17 receptor (IL-17RA). We report here that the IL-17RA-related molecule, IL-17RC is the receptor for IL-17F. Notably, both IL-17A and IL-17F bind to IL-17RC with high affinity, leading us to suggest that a soluble form of this molecule may serve as an effective therapeutic antagonist of IL-17A and IL-17F. We generated a soluble form of IL-17RC and demonstrate that it effectively blocks binding of both IL-17A and IL-17F, and that it inhibits signaling in response to these cytokines. Collectively, our work indicates that IL-17RC functions as a receptor for both IL-17A and IL-17F and that a soluble version of this protein should be an effective antagonist of IL-17A and IL-17F mediated inflammatory diseases.