IL1 RECEPTOR ANTAGONIST INTRACELLULAR VARIANTS

描述：（改编自申请人摘要）-本拟议研究的总体目标是研究IL-1Ra细胞内18 kDa亚型的存在及其在炎症性关节炎中的作用。分泌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细胞质中。1994年，他们发现了存在于中性粒细胞、肝细胞和巨噬细胞细胞质中的icIL-1RaII。要检验的假设是icIL-1RaI在炎症性关节炎中上调，这种蛋白表现出很强的抗炎作用。此外，滑膜成纤维细胞和软骨细胞中icIL-1RaI的过度表达将导致小鼠胶原诱导关节炎（CIA）中更有效的抗炎作用。这些研究将解决三个具体目标：1)确定icIL-1RaI在人类类风湿性关节炎（RA）和小鼠CIA关节中的存在和作用；2)通过转基因和敲除小鼠研究icIL-1RaI在CIA中的作用；3)研究icIL-1RaI对类风湿性滑膜炎SCID小鼠软骨破坏机制的影响。这些研究将研究icIL-1RaI在滑膜成纤维细胞和关节软骨细胞中的体内功能。这些研究与类风湿性关节炎和骨关节炎直接相关，其中IL-1通过诱导滑膜成纤维细胞和关节软骨细胞中金属蛋白酶的产生和释放而被认为是组织破坏的中介。IL-1Ra不仅抑制IL-1与细胞表面受体的结合，而且他们假设IL-1Ra的细胞内异构体在细胞内会表现出额外的抗炎作用。

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.