A cytokine protein-protein interaction network for identifying key molecules in rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory disease of the synovial joints. Though the current RA therapeutics such as disease-modifying antirheumatic drugs (DMARDs), nonsteroidal anti-inflammatory drugs (NSAIDs) and biologics can halt the progression of the disease, none of these would either dramatically reduce or cure RA. So, the identification of potential therapeutic targets and new therapies for RA are active areas of research. Several studies have discovered the involvement of cytokines in the pathogenesis of this disease. These cytokines induce signal transduction pathways in RA synovial fibroblasts (RASF). These pathways share many signal transducers and their interacting proteins, resulting in the formation of a signaling network. In order to understand the involvement of this network in RA pathogenesis, it is essential to identify the key transducers and their interacting proteins that are part of this network. In this study, based on a detailed literature survey, we have identified a list of 12 cytokines that induce signal transduction pathways in RASF. For these cytokines, we have built a signaling network using the protein-protein interaction (PPI) data that was obtained from public repositories such as HPRD, BioGRID, MINT, IntAct and STRING. By combining the network centrality measures with the gene expression data from the RA related microarrays that are available in the open source Gene Expression Omnibus (GEO) database, we have identified 24 key proteins of this signaling network. Two of these 24 are already drug targets for RA, and of the remaining, 12 have direct PPI links to some of the current drug targets of RA. Therefore, these key proteins seem to be crucial in the pathogenesis of RA and hence might be treated as potential drug targets.

类风湿关节炎（Rheumatoid arthritis, RA）是一种累及滑膜关节的慢性炎症性疾病。尽管当前的RA治疗手段如改善病情抗风湿药（disease-modifying antirheumatic drugs, DMARDs）、非甾体抗炎药（nonsteroidal anti-inflammatory drugs, NSAIDs）及生物制剂可阻断疾病进展，但上述疗法均无法显著缓解病情或治愈RA。因此，发掘RA潜在治疗靶点与新型治疗方案仍是当前研究的热点领域。多项研究已证实细胞因子参与了该病的发病机制。这些细胞因子可在类风湿关节炎滑膜成纤维细胞（RA synovial fibroblasts, RASF）中诱导信号转导通路，且这些通路共享大量信号转导分子及其互作蛋白，进而形成复杂的信号网络。为阐明该信号网络在RA发病机制中的作用，明确该网络中的关键转导分子及其互作蛋白至关重要。本研究通过全面的文献调研，筛选出12种可在RASF中诱导信号转导通路的细胞因子。基于从HPRD、BioGRID、MINT、IntAct及STRING等公共数据库获取的蛋白质相互作用（protein-protein interaction, PPI）数据，我们构建了上述细胞因子对应的信号网络。结合网络中心性分析方法与开源数据库基因表达综合数据库（Gene Expression Omnibus, GEO）中收录的RA相关微阵列基因表达数据，我们从该信号网络中筛选出24种关键蛋白。其中2种蛋白已被证实为RA的临床药物靶点，剩余22种中有12种与当前已获批的RA药物靶点存在直接PPI关联。因此，这些关键蛋白在RA发病机制中发挥关键作用，有望成为潜在的RA治疗新靶点。