RESUMEN
IL-22 is an IL-10 homologue that binds to and signals through the class II cytokine receptor heterodimer IL-22RA1/CRF2-4. IL-22 is produced by T cells and induces the production of acute-phase reactants in vitro and in vivo, suggesting its involvement in inflammation. Here we report the identification of a class II cytokine receptor designated IL-22RA2 (IL-22 receptor-alpha 2) that appears to be a naturally expressed soluble receptor. IL-22RA2 shares amino acid sequence homology with IL-22RA1 (also known as IL-22R, zcytor11, and CRF2-9) and is physically adjacent to IL-20Ralpha and IFN-gammaR1 on chromosome 6q23.3-24.2. We demonstrate that IL-22RA2 binds specifically to IL-22 and neutralizes IL-22-induced proliferation of BaF3 cells expressing IL-22 receptor subunits. IL-22RA2 mRNA is highly expressed in placenta and spleen by Northern blotting. PCR analysis using RNA from various tissues and cell lines showed that IL-22RA2 was expressed in a range of tissues, including those in the digestive, female reproductive, and immune systems. In situ hybridization revealed the dominant cell types expressing IL-22RA2 were mononuclear cells and epithelium. Because IL-22 induces the expression of acute phase reactants, IL-22RA2 may play an important role as an IL-22 antagonist in the regulation of inflammatory responses.
Asunto(s)
Interleucinas/antagonistas & inhibidores , Receptores de Interleucina/fisiología , Secuencia de Aminoácidos , Animales , Linfocitos B/metabolismo , Secuencia de Bases , Northern Blotting , Carcinoma/metabolismo , Línea Celular , Mapeo Cromosómico , Cromosomas Humanos Par 6/genética , Células Epiteliales/metabolismo , Femenino , Genes , Humanos , Sistema Inmunológico/metabolismo , Tejido Linfoide/metabolismo , Ratones , Datos de Secuencia Molecular , Monocitos/metabolismo , Proteínas de Neoplasias/biosíntesis , Especificidad de Órganos , Neoplasias Ováricas/metabolismo , Placenta/metabolismo , Reacción en Cadena de la Polimerasa , ARN Mensajero/biosíntesis , Mapeo de Híbrido por Radiación , Receptores de Interleucina/genética , Receptores de Interleucina/aislamiento & purificación , Proteínas Recombinantes de Fusión/metabolismo , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Piel/metabolismo , Bazo/metabolismo , Transfección , Interleucina-22RESUMEN
A structural, profile-based algorithm was used to identify interleukin 20 (IL-20), a novel IL-10 homolog. Chromosomal localization of IL-20 led to the discovery of an IL-10 family cytokine cluster. Overexpression of IL-20 in transgenic (TG) mice causes neonatal lethality with skin abnormalities including aberrant epidermal differentiation. Recombinant IL-20 protein stimulates a signal transduction pathway through STAT3 in a keratinocyte cell line, demonstrating a direct action of this ligand. An IL-20 receptor was identified as a heterodimer of two orphan class II cytokine receptor subunits. Both receptor subunits are expressed in skin and are dramatically upregulated in psoriatic skin. Taken together, these results demonstrate a role in epidermal function and psoriasis for IL-20, a novel cytokine identified solely by bioinformatics analysis.