Inflammatory modulation of synovial fibroblasts in rheumatoid arthritis
Date
2017
Authors
Afzali, Maryam F., author
Legare, Marie E., advisor
Allen, Christopher, committee member
Goodrich, Laurie, committee member
Hanneman, William, committee member
Tjalkens, Ronald, committee member
Journal Title
Journal ISSN
Volume Title
Abstract
Rheumatoid arthritis (RA) has a prevalence of 1-2% and is one of the more common causes of chronic morbidity among people over 65 years of age. It is characterized by hyperplasia of fibroblast-like synoviocytes (FLS) within the synovium and recruitment of multiple leukocyte populations that drive the inflammatory process. Although disease etiology is unknown, it is thought that both genetic and environmental factors trigger the onset of RA. A key mediator of cellular inflammation and joint destruction in rheumatoid arthritis (RA) is the presence of fibroblast-like synoviocytes (FLS), a unique cell type that distinguishes RA from other inflammatory conditions of the joint. Due to their presence within the disease, FLS represent a possible target for next generation RA therapeutics, used in conjunction with immunomodulators, to control disease pathology without augmenting immunosuppression. The complex network of signal transduction pathways controlling FLS include inflammatory proteins such as cytokines, matrix metalloproteinases, cyclooxygenase (COX-2), mitogen-activated protein kinase (MAPK), nuclear factor kappa-B (NF-kB), and janus kinase (JAK-STAT), all of which have been implicated in the pathogenesis of RA. Under rheumatoid conditions, FLS express the tumor necrosis factor (TNF)-recognition complex (TNFR1, TNFR2, VCAM-1 and ICAM-1), which induces local macrophage activation and leads to downstream NF-kB signaling, that is partially responsible for propagating inflammatory damage within the joint. It is postulated that specific inhibition of NF-kB signaling in this system could mitigate FLS-driven inflammation without the negative off-target effects of global immune suppression. We investigated into C-DIM mechanism of action, DIM-C-pPhCl was examined in the RAW264.7 macrophage cell line treated with LPS to stimulate cytokine production. DIM-C-pPhCl treatment reduced the expression of inflammatory proteins such as NF-κB, iNOS, COX-2, and prostaglandin production following LPS stimulation. In addition, DIM-C-pPhCl treatment increased the amount of nuclear p65 and Nurr1 protein. As a final investigation into the mechanism of action of C-DIM12, was examined in primary murine synovial fibroblasts treated with TNF- to stimulate adhesion molecules and cytokine productions. These experiments provide evidence that NF-B directly mediates the induction of VCAM-1 in synovial fibroblasts by TNF- and furthermore C-DIM12 suppresses this activation. Demonstrating that C-DIM12 induces activity in synovial fibroblasts through a Nurr1 dependent mechanism. Providing a novel mechanism to decrease expression of NF-B regulated inflammatory genes in synovial fibroblast cells relevant to degenerative joint diseases.