RESUMO
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.
Assuntos
Interleucina-17/metabolismo , Receptores de Interleucina-17/metabolismo , Processamento Alternativo/imunologia , Animais , Ligação Competitiva/imunologia , Linhagem Celular , Cricetinae , Humanos , Mediadores da Inflamação/metabolismo , Mediadores da Inflamação/uso terapêutico , Interleucina-17/antagonistas & inibidores , Camundongos , Camundongos Endogâmicos BALB C , Dados de Sequência Molecular , Ligação Proteica/genética , Ligação Proteica/imunologia , Receptores de Interleucina-17/genética , Receptores de Interleucina-17/uso terapêutico , Especificidade da Espécie , TransfecçãoRESUMO
The ade6-M26 allele of Schizosaccharomyces pombe creates a well-defined meiotic recombination hot spot that requires a specific sequence, 5'-ATGACGT-3', and the Atf1*Pcr1 transcription factor for activity. We find that M26 stimulates the formation of meiosis-specific double-strand DNA breaks at multiple sites surrounding M26. Like hot spot activity, breakage requires the M26 heptamer, Pcr1, and the general recombination factor Rec12. When the M26 heptamer is moved to new positions within ade6, new break sites are observed spanning approximately 0.5-2 kb around the moved heptamer. Break frequency is strongly correlated with recombination frequency for these alleles. The occurrence of breaks at M26 suggests mechanistic similarities to hot spots in the distantly related yeast Saccharomyces cerevisiae.
Assuntos
Carboxiliases/genética , Quebra Cromossômica , Cromossomos Fúngicos/genética , DNA Fúngico/genética , Proteínas de Ligação a DNA/fisiologia , Meiose/genética , Recombinação Genética/genética , Proteínas de Saccharomyces cerevisiae , Proteínas de Schizosaccharomyces pombe/fisiologia , Schizosaccharomyces/genética , Fatores de Transcrição/fisiologia , Fator 1 Ativador da Transcrição , Fatores Ativadores da Transcrição , Alelos , Cromossomos Fúngicos/ultraestrutura , Reparo do DNA , DNA Fúngico/metabolismo , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a RNA , Sequências Reguladoras de Ácido Nucleico , Saccharomyces cerevisiae/genética , Proteínas de Schizosaccharomyces pombe/genética , Especificidade da Espécie , Temperatura , Fatores de Transcrição/deficiência , Fatores de Transcrição/genéticaRESUMO
DNA breakage is intimately associated with meiotic recombination in the fission yeast Schizosaccharomyces pombe. Sites of prominent DNA breakage were found approximately 25 to approximately 200 kb apart in the genomic regions surveyed. We examined in detail a 501 kb region of chromosome I and found six sites, or tight clusters of sites, at which approximately 2%-11% of the DNA accumulated breaks in a rad50S mutant. In contrast to the discrete, widely spaced distribution of prominent break sites, recombination in this region was more uniformly distributed (0.7-1.6 cM/10 kb) whether the genetic interval tested contained no, one, or more such sites. We infer that although recombination depends upon DNA breakage, recombination often occurs remote from these sites (tens of kilobases away); we discuss mechanisms by which this may occur.