HMGB1 Promotes the Synthesis of Pro-IL-1β and Pro-IL-18 by Activation of p38 MAPK and NF-κB Through Receptors for Advanced Glycation End-products in Macrophages

The high mobility group box-1 (HMGB1) protein and NALP3 inflammasome have been identified to playimportant roles in inflammation and cancer pathogenesis, but the relationships between the two and cancerremain unclear. The current study investigated the relationship between HMGB1 and the NALP3 inflammasomein THP-1 macrophages. HMGB1 was found unable to activate the NALP3 inflammasome and failed to inducethe release of the IL-1β and IL-18 in THP-1 macrophages. HMGB1 was also found significantly enhanced theactivity of ATP to induce IL-1β and IL-18 by the induction of increased expression of pro-IL-1β and pro-IL-18.This process was dependent on activation of RAGE, MAPK p38 and NF-κB signaling pathway. These resultsdemonstrate that HMGB1 promotes the synthesis of pro-IL-1β and pro-IL-18 in THP-1 macrophages by theactivation of p38 MAPK and NF-κB through RAGE. HMGB1 likely plays an important role in the first step ofthe release of the IL-1β and IL-18, preparing for other cytokines to induce excessive release of IL-1β and IL-18which promote inflammation and cancer progression.