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

Qiang He,Tian-Hui Liu,Bao-En Wang,Xin-Min Li,Ping Wang,Hong You

doi:10.7314/apjcp.2012.13.4.1365

Abstract

The high mobility group box-1 (HMGB1) protein and NALP3 inflammasome have been identified to play important roles in inflammation and cancer pathogenesis, but the relationships between the two and cancer remain unclear. The current study investigated the relationship between HMGB1 and the NALP3 inflammasome in THP-1 macrophages. HMGB1 was found unable to activate the NALP3 inflammasome and failed to induce the release of the IL-1β and IL-18 in THP-1 macrophages. HMGB1 was also found significantly enhanced the activity 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 results demonstrate that HMGB1 promotes the synthesis of pro-IL-1β and pro-IL-18 in THP-1 macrophages by the activation of p38 MAPK and NF-κB through RAGE. HMGB1 likely plays an important role in the first step of the release of the IL-1β and IL-18, preparing for other cytokines to induce excessive release of IL-1β and IL-18 which promote inflammation and cancer progression.

Highlights

Current estimates suggest that about 25% of cancers are associated with chronic inflammation (Mantovani et al, 2008)
Can activate the NALP3 inflammasome, we examined the expression of cleaved caspase-1, but it was not detected high mobility group box-1 (HMGB1) promoted the synthesis of pro-IL-1β and proin the current study after with the addition of 100, 200, IL-18 through receptor for advanced glycation end products (RAGE) receptors
These data are consistent with the findings of the current study that found that HMGB1 alone cannot promote the release of IL-1β and IL-18

Summary

Introduction

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). 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

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Conclusion