HMGB1 Promotes Pro-IL-1β and Pro-IL-18 Synthesis through p38 MAPK and RAGE

Current estimates suggest that about 25% of cancers are associated with chronic inflammation (Mantovani et al., 2008). Many cytokines and mediators of inflammation are known to have an important role in cancer pathogenesis, but the underlying mechanisms are still not fully understood. The high mobility group box 1 (HMGB1) protein was originally identified as a nuclear protein that can regulate transcription by changing DNA helical structure, recent studies suggest that the HMGB1 has been implicated in several disease states, including sepsis, arthritis, ischemiareperfusion injury, and cancer (Sims et al., 2010; Tang et al., 2010). Necrotic Cancer cells can release HMGB1 into the local microenvironment. HMGB1 is also actively secreted by inflammatory cells, such as macrophages, acting as an endogenous danger signal and binding with high affinity to several receptors including the receptor for advanced glycation end products (RAGE), Tolllike receptors (TLR)-2, TLR-4 and TLR-9 (Park et al., 2006; Sims et al., 2010). Although a number of clinical studies have suggested that overexpression of HMGB1 is associated with cancer (Tang et al., 2010), but the mechanisms are still mysterious. Recently many studies have demonstrated that