High-mobility group box 1 exacerbates concanavalin A-induced hepatic injury in mice

Abstract

High-mobility group box 1 (HMGB1) is a nuclear factor released extracellularly as an early endogenous alarmin of inflammation following injury and as a late mediator of lethality in sepsis. Although HMGB1 has been implicated in acute lung injury, rheumatoid arthritis, and allograft rejection, its role in T-cell mediated hepatitis remains obscure. Here, we investigated the role and the underlying mechanisms of HMGB1 in concanavalin A (Con A) induced hepatic injury. We demonstrate that high levels of HMGB1 were detected in the necrotic area and in the cytoplasm of hepatocytes after Con A treatment. Administration of exogenous recombinant HMGB1 enhanced Con A-induced hepatitis, while blockade of HMGB1 protected animals from T cell-mediated hepatitis as evidenced by decreased serum transaminase, associated with reduced hepatic necrosis and mortality. Blockade of HMGB1 by a neutralizing antibody inhibited proinflammatory cytokine production, NFκB activity, and the late stage of T/NKT cell activation. These finding thus suggest a pivotal factor of HMGB1 in Con A-induced hepatitis. Blockage of extracellular HMGB1 may represent a novel therapeutic strategy to prevent hepatic injury in T cell-mediated hepatitis.

Quercetin Protects Mice from ConA-Induced Hepatitis by Inhibiting HMGB1-TLR Expression and Down-Regulating the Nuclear Factor Kappa B Pathway

“…Studies have suggested that TLR-mediated signals are involved in almost all liver diseases [13,[18][19][20], and recent studies implicating TLR2 and TLR4 signaling in ConAinduced liver injury are of particular importance [14,19,21,22]. Also, expression of TLR2 and TLR4 is upregulated in liver cells during ConA-induced hepatic injury [14,19,22].…”

“…Also, expression of TLR2 and TLR4 is upregulated in liver cells during ConA-induced hepatic injury [14,19,22]. Furthermore, mice deficient in TLR2 or TLR4 are protected from ConA-induced hepatic injury as compared with wild-type mice [14,21].…”

“…HMGB1 has been shown to be involved in liver damage in different models of acute liver injury [12][13][14][15][16]. Recently, our research team reported that high levels of HMGB1 are present in necrotic areas and hepatocyte cytoplasm after ConA treatment [17].…”

“…Moreover, anti-HMGB1 treatment with antibodies, specific antagonists, or other pharmacologic agents was found to be beneficial in many preclinical models of inflammatory disease; such treatment ameliorated the severity of diseases or reduced mortality [9,10]. Therefore, HMGB1 may be a therapeutic target for inflammatory liver diseases caused by injury, ischemia, or infection [9,14,17].…”

Emerging Role of High-Mobility Group Box 1 (HMGB1) in Liver Diseases

“…Blocking HMGB1 release or activity by ethyl pyruvate and HMGB1-neutralizing antibody prevents APAP-induced hepatotoxicity and restores liver structure by inhibition of oxidative injury and inflammation (91,92). In addition, HMGB1 cytoplasmic translocation and release during tissue damage and cell death promotes pathological processes in several drug-induced acute liver failures (93,94).…”