Aryl Hydrocarbon Receptor antagonism attenuates inflammatory and growth factor gene expression in fibroblast like synoviocytes from individuals with rheumatoid arthritis.
Open Access
Author:
Hughes, Jarod Michael
Area of Honors:
Veterinary and Biomedical Sciences
Degree:
Bachelor of Science
Document Type:
Thesis
Thesis Supervisors:
Gary H. Perdew, Thesis Supervisor Gary H. Perdew, Thesis Honors Advisor Andrew David Patterson, Faculty Reader
Rheumatoid arthritis is a chronic autoimmune disease affecting the synovium of joints. The disease is characterized by chronic innate and adaptive inflammatory signaling, mediated at least in part by a number of pro-inflammatory cytokines including interleukin 1 beta (IL1B). The genes IL1B and cyclooxygenase 2 are upregulated in this proinflammatory environment and create a positive feedback-signaling loop between synoviocytes and immune cells. In addition, vascular growth factor A, which is induced during inflammation and contributes to invasive potential of synoviocytes into bone as the rheumatoid arthritis process progresses. The role of the Aryl hydrocarbon receptor (AHR) in IL1B-mediated expression of pro-inflammatory and mitogenic genes associated with rheumatoid arthritis pathology was examined.
Results revealed that AHR antagonism with the compound GNF-351 attenuates pro-inflammatory gene expression in primary fibroblast like synoviocytes from individuals with rheumatoid arthritis. Using qPCR ,siRNA, knockdown of AHR, and ELISA results revealed that GNF-351 exerts its effects through AHR antagonism and represses both mRNA levels and secreted protein levels of a number of pro-inflammatory genes. This study shows that AHR antagonism is a potential approach to treat rheumatoid arthritis induced inflammation.
