4-PHENYLBUTYRIC ACID AMELIORATES LUPUS HEPATITIS AND NEPHRITIS THROUGH SUPPRESSION OF NF-KB ACTIVATION IN EXPERIMENTAL LUPUS MODEL

Background: Systemic lupus erythematosus (SLE) is an autoimmune disease presenting diverse manifestation involving multiple organs, such as liver and kidney. Endoplasmic reticulum (ER) stress has been revealed as the one of the contributing factors of lupus pathogenesis. Objectives: The purpose of the present study was to investigate whether ER stress inhibition suppresses organ inflammation including liver and kidney in lupus murine model and the activation of mitogen activated protein kinases (MAPK) and NF-kB. Methods: A murine lupus model was induced through a 4-week treatment with Resiquimod, a toll-like receptor agonist 7. From the 8 week, the mice were treated with phosphate buffered saline, 4-phenylbutyric acid (4-PBA), and dexamethasone for 4 weeks. The increment of body weight, liver weight, inflammation mediator level, and the pathology of hepatitis and nephritis were analyzed at 12 weeks of age. The level of phosphorylated MAPK expression and activation of NF-kb were also evaluated. Results: 4-PBA-treated group showed lower level of body weight increment with liver to body weight ratio compared with vehicle-treated group. 4-PBA group showed decreased inflammatory cell infiltration and fibrosis in the histologic finding of liver and kidney and lower level of inflammatory mediators, including TNF-α and IL-6, compared to vehicle-group. GRP78 and CHOP expression was decreased in the spleen of 4-PBA treated mice compared to vehicle-treated mice and 4-PBA group showed the lower expression level of phosphorylated JNK, ERK, p38 and NF-kB of the spleen. Conclusion: Our results suggest that 4-PBA attenuates the inflammation on liver and kidney of experimental lupus model through suppression of MAPK and NF-kB activation. Thus, inhibition of ER stress could be function as anti-inflammatory therapeutics for SLE. Abstract THU0209 – Figure 1 REFERENCES: [1] Navid F, Colbert RA. Causes and consequences of endoplasmic reticulum stress in rheumatic disease. Nat Rev Rheumatol2017;13:25-40 [2] Hosoi T, Ozawa K. Endoplasmic reticulum stress in disease: mechanisms and therapeutic opportunities. Clin Sci (Lond)2009;118:19-29 Disclosure of Interests: None declared DOI: 10.1136/annrheumdis-2019-eular.5589Citation: Ann Rheum Dis, volume 78, supplement 2, year 2019, page A383Session: SLE, Sjögren’s and APS - etiology, pathogenesis and animal models (Scientific Abstracts)