HMGB-1 induces IL-6 production in human synovial fibroblasts through c-Src, Akt and NF-κB pathways

High mobility group box chromosomal protein 1 (HMGB‐1) is a widely studied, ubiquitous nuclear protein that is present in eukaryotic cells, and plays a crucial role in inflammatory response. However, the effects of HMGB‐1 on human synovial fibroblasts are largely unknown. In this study, we investigated the intracellular signaling pathway involved in HMGB‐1‐induced IL‐6 production in human synovial fibroblast cells. HMGB‐1 caused concentration‐ and time‐dependent increases in IL‐6 production. HMGB‐1‐mediated IL‐6 production was attenuated by receptor for advanced glycation end products (RAGE) monoclonal antibody (Ab) or siRNA. Pretreatment with c‐Src inhibitor (PP2), Akt inhibitor and NF‐κB inhibitor (pyrrolidine dithiocarbamate and L‐1‐tosylamido‐2‐phenylenylethyl chloromethyl ketone) also inhibited the potentiating action of HMGB‐1. Stimulation of cells with HMGB‐1 increased the c‐Src and Akt phosphorylation. HMGB‐1 increased the accumulation of p‐p65 in the nucleus, as well as NF‐κB luciferase activity. HMGB‐1‐mediated increase of NF‐κB luciferase activity was inhibited by RAGE Ab, PP2 and Akt inhibitor or RAGE siRNA, or c‐Src and Akt mutant. Our results suggest that HMGB‐1‐increased IL‐6 production in human synovial fibroblasts via the RAGE receptor, c‐Src, Akt, p65, and NF‐κB signaling pathways. J. Cell. Physiol. 226: 2006–2015, 2011. © 2010 Wiley‐Liss, Inc.