In rheumatoid arthritis (RA) inflammatory cytokines produced by synovial (joint) cells drive disease pathogenesis by activating cells in inflamed joints and inducing recruitment of inflammatory cells. Key pathogenic roles for the cytokines tumor necrosis factor (TNF) and interleukin-6 (IL-6) in human RA have been demonstrated by the efficacy of therapies that specifically target these cytokines using blocking antibodies or soluble receptors. The long term goals of this project are to understand how cytokines activate synovial cells to drive disease pathogenesis and cause morbidity, and to elucidate mechanisms that regulate production of pathogenic cytokines in the context of RA synovitis. An associated goal is to use this knowledge to develop safer and more effective therapies that selectively target disease-related mechanisms of cytokine production and function, while preserving aspects of host defense. This project has focused on two key synovial cell types important in RA pathogenesis, fibroblast-like synoviocytes (FLS) and synovial macrophages (previously termed type A synoviocytes). In the previous project period, we found that TNF induces a sustained inflammatory response in FLS, including prolonged activation of NF-kB and transcription of genes that encode IL-6, IL-8 and MMPs. We propose that lack of effective deactivation of inflammatory responses in FLS, which contrasts with homeostatic feed-back inhibition (`tolerization') that deactivates hematopoietic cells, contributes to unremitting inflammation in chronic RA. Two complementary mechanisms underlying prolonged TNF-induced activation and inflammatory gene expression in FLS are ineffective termination of TNF and NF-kB signaling, and ineffective silencing of inflammatory gene loci by epigenetic chromatin-mediated mechanisms. Thus, ineffective engagement of homeostatic signaling and epigenetic mechanisms that terminate inflammatory responses in other cell types (including macrophages) leads to sustained inflammatory responses in FLS. Based on our overarching hypothesis that augmenting homeostatic mechanisms represents an effective therapeutic approach to suppress inflammation, we further investigated mechanisms underlying prolonged TNF-induced signaling and inflammatory gene expression. A mechanism underlying prolonged inflammatory gene expression is sustained opening of chromatin and hyperacetylation of histones, which results in sensitivity to inhibition by I-BET, a small molecule that blocks interactions of transcriptional co- activators with acetylated histones. A functional consequence of prolonged FLS activation by TNF is production of soluble factors that alter macrophage polarization and inflammatory mediator production, thus identifying a new function of FLS. In this project, we will investigate epigenetic mechanisms that regulate inflammatory activation of FLS, and the functional consequences of prolonged FLS activation on macrophage phenotype and in vivo arthritis models.
NIH ExPorter
NIH ExPorter