RESUMO
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.
Assuntos
Interleucinas/antagonistas & inibidores , Receptores de Interleucina/fisiologia , Sequência de Aminoácidos , Animais , Linfócitos B/metabolismo , Sequência de Bases , Northern Blotting , Carcinoma/metabolismo , Linhagem Celular , Mapeamento Cromossômico , Cromossomos Humanos Par 6/genética , Células Epiteliais/metabolismo , Feminino , Genes , Humanos , Sistema Imunitário/metabolismo , Tecido Linfoide/metabolismo , Camundongos , Dados de Sequência Molecular , Monócitos/metabolismo , Proteínas de Neoplasias/biossíntese , Especificidade de Órgãos , Neoplasias Ovarianas/metabolismo , Placenta/metabolismo , Reação em Cadeia da Polimerase , RNA Mensageiro/biossíntese , Mapeamento de Híbridos Radioativos , Receptores de Interleucina/genética , Receptores de Interleucina/isolamento & purificação , Proteínas Recombinantes de Fusão/metabolismo , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Pele/metabolismo , Baço/metabolismo , Transfecção , Interleucina 22RESUMO
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.
Assuntos
Epiderme/imunologia , Interleucinas/genética , Receptores de Citocinas/genética , Receptores de Citocinas/imunologia , Animais , Linhagem Celular , Mapeamento Cromossômico , Clonagem Molecular , Proteínas de Ligação a DNA/metabolismo , Dimerização , Epiderme/química , Epiderme/patologia , Expressão Gênica/imunologia , Humanos , Interleucina-10/genética , Interleucina-10/imunologia , Interleucinas/química , Interleucinas/imunologia , Queratinócitos/citologia , Queratinócitos/imunologia , Queratinas/genética , Camundongos , Camundongos Transgênicos , Dados de Sequência Molecular , Psoríase/imunologia , Psoríase/patologia , Receptores de Citocinas/química , Fator de Transcrição STAT3 , Homologia de Sequência de Aminoácidos , Transativadores/metabolismo , Regulação para Cima/imunologiaRESUMO
Cytokines are important in the regulation of haematopoiesis and immune responses, and can influence lymphocyte development. Here we have identified a class I cytokine receptor that is selectively expressed in lymphoid tissues and is capable of signal transduction. The full-length receptor was expressed in BaF3 cells, which created a functional assay for ligand detection and cloning. Conditioned media from activated human CD3+ T cells supported proliferation of the assay cell line. We constructed a complementary DNA expression library from activated human CD3+ T cells, and identified a cytokine with a four-helix-bundle structure using functional cloning. This cytokine is most closely related to IL2 and IL15, and has been designated IL21 with the receptor designated IL21 R. In vitro assays suggest that IL21 has a role in the proliferation and maturation of natural killer (NK) cell populations from bone marrow, in the proliferation of mature B-cell populations co-stimulated with anti-CD40, and in the proliferation of T cells co-stimulated with anti-CD3.
Assuntos
Linfócitos B/imunologia , Interleucinas/fisiologia , Células Matadoras Naturais/imunologia , Receptores de Interleucina/fisiologia , Linfócitos T/imunologia , Sequência de Aminoácidos , Animais , Células da Medula Óssea , Antígenos CD40/metabolismo , Linhagem Celular , Clonagem Molecular , Etiquetas de Sequências Expressas , Humanos , Subunidade alfa de Receptor de Interleucina-21 , Interleucinas/genética , Interleucinas/isolamento & purificação , Leucopoese , Ligantes , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Conformação Proteica , Receptores de Interleucina/genética , Receptores de Interleucina/isolamento & purificação , Receptores de Interleucina-21 , Distribuição TecidualRESUMO
B cells are important in the development of autoimmune disorders by mechanisms involving dysregulated polyclonal B-cell activation, production of pathogenic antibodies, and co-stimulation of autoreactive T cells. zTNF4 (BLyS, BAFF, TALL-1, THANK) is a member of the tumour necrosis factor (TNF) ligand family that is a potent co-activator of B cells in vitro and in vivo. Here we identify two receptors for zTNF4 and demonstrate a relationship between zTNF4 and autoimmune disease. Transgenic animals overexpressing zTNF4 in lymphoid cells develop symptoms characteristic of systemic lupus erythaematosus (SLE) and expand a rare population of splenic B-Ia lymphocytes. In addition, circulating zTNF4 is more abundant in NZBWF1 and MRL-lpr/lpr mice during the onset and progression of SLE. We have identified two TNF receptor family members, TACI and BCMA, that bind zTNF4. Treatment of NZBWF1 mice with soluble TACI-Ig fusion protein inhibits the development of proteinuria and prolongs survival of the animals. These findings demonstrate the involvement of zTNF4 and its receptors in the development of SLE and identify TACI-Ig as a promising treatment of autoimmune disease in humans.
