IL1 RECEPTOR ANTAGONIST INTRACELLULAR VARIANTS

描述：(改编自申请人的摘要)-这项拟议研究的总体目标是研究IL-1ra的18 kDa细胞内异构体的存在及其在炎症性关节炎中的作用。分泌型sIL-1ra是单核细胞、巨噬细胞和中性粒细胞的主要产物。18 kDa的icIL-1RaI存在于上皮细胞、成纤维细胞、单核细胞和巨噬细胞的胞浆中。1994年，他们发现了ICIL-1RaII，它存在于中性粒细胞、肝细胞和巨噬细胞的细胞质中。需要检验的假设是，icIL-1RaI在炎症性关节炎中上调，该蛋白显示出强大的抗炎作用。此外，在滑膜成纤维细胞和软骨细胞中过表达icIL-1RaI将在胶原性关节炎(CIA)小鼠中产生更强的抗炎作用。这些研究将致力于三个具体目标：1)确定icIL-1RaI在人类类风湿关节炎(RA)和CIA小鼠关节中的存在和作用；2)通过使用转基因和基因敲除小鼠来检测icIL-1RaI在CIA中的作用；以及3)检测icIL-1RaI在类风湿滑膜炎SCID小鼠模型中对软骨破坏机制的影响。这些研究将研究滑膜成纤维细胞和关节软骨细胞中ICIL-1RaI的体内功能。这些研究都与类风湿性关节炎和骨性关节炎直接相关，在骨性关节炎中，IL-1通过诱导滑膜成纤维细胞和关节软骨细胞产生和释放金属蛋白酶而被认为是组织破坏的介质。SIL-1ra不仅抑制IL-1与细胞表面受体的结合，而且还假设IL-1ra的细胞内异构体在细胞内具有额外的抗炎作用。

DESCRIPTION: (Adapted from the applicant's abstract) - The overall objective of this proposed research is to study the presence of the 18 kDa intracellular isoform of IL-1Ra and its role in inflammatory arthritis. The secretory sIL-1Ra is a major product of monocytes, macrophages, and neutrophils. The 18 kDa icIL-1RaI is found in the cytoplasm of epithelial cells, fibroblasts, monocytes, and macrophages. In 1994, they found icIL-1RaII, which is present in the cytoplasm of neutrophils, hepatocytes, and macrophages. The hypothesis to be examined is that icIL-1RaI is upregulated in inflammatory arthritis and this protein exhibits strong antiinflammatory effects. Furthermore, over-expression of icIL-1RaI in synovial fibroblasts and chondrocytes will lead to more potent antiinflammatory effects in collagen-induced arthritis (CIA) in mice. Three specific aims will be addressed in these studies: 1) To determine the presence and effects of icIL-1RaI in the joints from both human rheumatoid arthritis (RA) and CIA in mice; 2) to examine the effects of icIL-1RaI in CIA through using transgenic and knockout mice; and 3) to examine the effects of icIL-1RaI on the mechanisms of cartilage destruction in the SCID mouse model of rheumatoid synovitis. These studies will study the in vivo function icIL-1RaI in synovial fibroblasts and articular chondrocytes. These studies are directly related to both RA and osteoarthritis where IL-1 has been implicated as a mediator of tissue destruction through inducing the production and release of metallo-proteinases in synovial fibroblasts and articular chondrocytes. Not only does sIL-1Ra inhibit the binding of IL-1 to cell surface receptors, but they hypothesize that the intracellular isoforms of IL-1Ra will exhibit additional antiinflammatory effect inside cells.