High Mobility Group Protein B1 (Hmgb1) Interacts With Receptor For Advanced Glycation End Products (Rage) To Promote Airway Smooth Muscle Cell Proliferation Through Erk And Nf-Kappa B Pathways

Background: High-mobility graoup box protein 1 (HMGB1) has been shown to mediate a wide range of pathologic responses by interacting with RAGE (receptor for advanced glycation endproducts) and TLRs (Toll-like receptors). Our previous study showed that HMGB1 has been involved in pathogenesis of airway remodeling in an allergen induced chronic mice asthma model. Increased airway smooth muscle (ASM) mass is a vital feature of airway remodeling. Objective: To evaluate the effect of HMGB1 on proliferation of ASMs and the underlying mechanisms. Methods: Rat airway smooth muscle cells (RASMs) were obtained by primary explant techniques. We investigated the effect of HMGB1 on the proliferation of RASMs. To identify which receptors and signaling pathways be involved in proliferation of RASMs, we performed western blot and CCK-8 assay by specific receptor blockade and inhibition of MAPK (p38, JNK and ERK) and NF-kappa B signaling pathways. Results: HMGB1 stimulated RASMs proliferation in a dose- and time-dependent manner and also increased proliferating cell nuclear antigen (PCNA) and RAGE expression of RASMs. The inhibitor of RAGE, but not TLR2 and TLR4, reversed HMGB1-induced RASM proliferation and PCNA expression. Incubation of RASMs with HMGB1 caused a rapid increase in P65 and ERK phosphorylation. RASM proliferation and PCNA expression toward HMGB1 were significantly inhibited by the inhibitors of ERK and NF-kappa B. Conclusion: HMGB1 induces proliferation of RASMs through a RAGE-dependent activation of ERK and NF-kappa B signaling pathways.