AB0056 Hmgb1 regulates hypoxia-inducible factor 1alpha expression and function in synovial fibroblasts from patients with rheumatoid arthritis. (23rd January 2014)

• Record Type: Journal Article
• Authors: Park, S. Y.; Lee, H. R.; Kim, H. Y.; Baek, S. H.; Kim, C. D.
• Is Part Of: Annals of the rheumatic diseases. Volume 72:Supplement 3(2013)
• Page Start: A802
• Page End: A803
• Publication Date: 2014-01-23
• Subjects: Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2013-eular.2379
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : Background: High mobility group box chromosomal protein 1 (HMGB1) is a nuclear DNA binding protein that is secreted into extracellular medium by cellular activation and proinflammatory response, and promotes inflammation. HMGB1 is known as ligand for TLR4 that produces TNF-a and IL-8 (1, 2 ). Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric transcription factor which is composed of an alpha and beta subunit. HIF-1 has been reported as regulator of angiogenesis in rheumatoid arthritis (RA) (3, 4 ). Objectives: We investigated the role and molecular mechanism of HMGB1 in the expression and function of HIF-1α in synovial fibroblasts from patients with RA. Methods: HIF-1 activity and VEGF expression were measured by ELISA. Signaling and molecular events were analyzed by immunoblotting. Results: The expression of extracellular HMGB1 was increased in synovium of RA patients than OA patients. Treatment of RA synovial fibroblasts with HMGB1 increased HIF-1αexpression and HIF-1 activity. HMGB1 mediated production of VEGF was dependent upon HIF-1. When TLR4 was blocked by TLR4 siRNA or anti-TLR4 antibody, HIF-1αdidn't be increased, leading to abolish the increase in VEGF production. Image/graph: Conclusions: Our results suggest that HMGB1stimulation of HIF-1α expression and activity results in VEGF expression that is dependent upon TLR4. References: Bustin M, Reeves R. High-mobility-group chromosomal proteins: architectural components that facilitate chromatin function. Prog Nucleic Acid Res Mol Biol 1996, 54:35-100. Hamada T, Torikai M, Kuwazuru A, et al. Extracellular high mobility group box chromosomal protein 1 is a coupling factor for hypoxia and inflammation in arthritis. Arthritis Rheum 2008, 58:2675-2685, Imtiyaz HZ, Simon MC. Hypoxia-inducible factors as essential regulators of inflammation. Curr Top Microbiol Immunol 2010, 345:105-120. Giatromanolaki A, Sivridis E, Maltezos E, et al. Upregulated hypoxia inducible factor-1alpha and -2alpha pathway in rheumatoid arthritis and osteoarthritis. Arthritis Res Ther 2003, 5:R193–201. Disclosure of Interest: None Declared