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.
Conclusions Our results suggest that HMGB1stimulation of HIF-1α expression and activity results in VEGF expression that is dependent upon TLR4.
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