RESUMO
HLA-A*11:152 differs from A*11:01:01 by a single nucleotide at position 266 in Exon 2.
Assuntos
Alelos , Loci Gênicos , Antígeno HLA-A11/genética , Células-Tronco Hematopoéticas/imunologia , Polimorfismo de Nucleotídeo Único , Substituição de Aminoácidos , Povo Asiático , Sequência de Bases , Éxons , Expressão Gênica , Antígeno HLA-A11/imunologia , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/citologia , Teste de Histocompatibilidade , Humanos , Dados de Sequência Molecular , Alinhamento de Sequência , Análise de Sequência de DNA , Doadores não RelacionadosRESUMO
Overexpression of interleukin (IL-)17 has recently been shown to be associated with a number of pathological conditions. Because IL-17 is found at high levels in the synovial fluid surrounding cartilage in patients with inflammatory arthritis, the present study determined the direct effect of IL-17 on articular cartilage. As shown herein, IL-17 was a direct and potent inducer of matrix breakdown and an inhibitor of matrix synthesis in articular cartilage explants. These effects were mediated in part by leukemia inhibitory factor (LIF), but did not depend on interleukin-1 activity. The mechanism whereby IL-17 induced matrix breakdown in cartilage tissue appeared to be due to stimulation of activity of aggrecanase(s), not matrix metalloproteinase(s). However, IL-17 upregulated expression of matrix metalloproteinase(s) in chondrocytes cultured in monolayer. In vivo, IL-17 induced a phenotype similar to inflammatory arthritis when injected into the intra-articular space of mouse knee joints. Furthermore, a related protein, IL-17E, was found to have catabolic activity on human articular cartilage. This study characterizes the mechanism whereby IL-17 acts directly on cartilage matrix turnover. Such findings have important implications for the treatment of degenerative joint diseases such as arthritis.
Assuntos
Cartilagem Articular/efeitos dos fármacos , Interleucina-17/farmacologia , Animais , Western Blotting , Cartilagem Articular/citologia , Cartilagem Articular/metabolismo , Bovinos , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Técnicas de Cultura , Citocinas/farmacologia , Endopeptidases/metabolismo , Feminino , Injeções Intra-Articulares , Metaloproteinases da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico/fisiologia , Patela/metabolismo , Proteoglicanas/efeitos dos fármacos , Proteoglicanas/metabolismo , Suínos , Regulação para CimaRESUMO
The proinflammatory cytokine interleukin 17 (IL-17) is the founding member of a family of secreted proteins that elicit potent cellular responses. We report a novel human IL-17 homolog, IL-17F, and show that it is expressed by activated T cells, can stimulate production of other cytokines such as IL-6, IL-8 and granulocyte colony-stimulating factor, and can regulate cartilage matrix turnover. Unexpectedly, the crystal structure of IL-17F reveals that IL-17 family members adopt a monomer fold typical of cystine knot growth factors, despite lacking the disulfide responsible for defining the canonical "knot" structure. IL-17F dimerizes in a parallel manner like neurotrophins, and features an unusually large cavity on its surface. Remarkably, this cavity is located in precisely the same position where nerve growth factor binds its high affinity receptor, TrkA, suggesting further parallels between IL-17s and neurotrophins with respect to receptor recognition.