RESUMO
IDO2 is one of two closely related tryptophan catabolizing enzymes induced under inflammatory conditions. In contrast to the immunoregulatory role defined for IDO1 in cancer models, IDO2 has a proinflammatory function in models of autoimmunity and contact hypersensitivity. In humans, two common single-nucleotide polymorphisms have been identified that severely impair IDO2 enzymatic function, such that <25% of individuals express IDO2 with full catalytic potential. This, together with IDO2's relatively weak enzymatic activity, suggests that IDO2 may have a role outside of its function in tryptophan catabolism. To determine whether the enzymatic activity of IDO2 is required for its proinflammatory function, we used newly generated catalytically inactive IDO2 knock-in mice together with established models of contact hypersensitivity and autoimmune arthritis. Contact hypersensitivity was attenuated in catalytically inactive IDO2 knock-in mice. In contrast, induction of autoimmune arthritis was unaffected by the absence of IDO2 enzymatic activity. In pursuing this nonenzymatic IDO2 function, we identified GAPDH, Runx1, RANbp10, and Mgea5 as IDO2-binding proteins that do not interact with IDO1, implicating them as potential mediators of IDO2-specific function. Taken together, our findings identify a novel function for IDO2, independent of its tryptophan catabolizing activity, and suggest that this nonenzymatic function could involve multiple signaling pathways. These data show that the enzymatic activity of IDO2 is required only for some inflammatory immune responses and provide, to our knowledge, the first evidence of a nonenzymatic role for IDO2 in mediating autoimmune disease.
Assuntos
Artrite/imunologia , Autoimunidade/imunologia , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Animais , Antígenos de Neoplasias/metabolismo , Linhagem Celular , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Técnicas de Introdução de Genes , Gliceraldeído-3-Fosfato Desidrogenase (Fosforiladora)/metabolismo , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Células HEK293 , Humanos , Inflamação/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/metabolismo , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
Building on Preston and Campbell's two-sex model of intergenerational transmission, this article provides a theoretical analysis of the dynamics of the racial distribution in black-white-mulatto systems. The author shows that "bounded" patterns of racial classification and switching imply long-run racial homogeneity in the absence of differential reproduction. Beyond the theoretical analysis, the author attempts to account for the dramatic growth of the white population share in Puerto Rico in the early 20th century. Because the effects of racial classification and differential reproduction were roughly offsetting, the observed growth of the white share can be attributed almost entirely to racial switching.