An overview on HMGB1 inhibitors as potential therapeutic agents in HMGB1-related pathologies
Section snippets
HMGB1 protein: physiological and pathological roles
High mobility group box (HMGB) is a family of three nuclear proteins present in mammals including HMGB1, HMGB2 and HMGB3 (Bustin, 1999, Bianchi and Beltrame, 2000). HMGB1 protein was first isolated almost 40 years ago as an abundant non-histone chromatin-associated protein with high electrophoretic mobility (Goodwin et al., 1973, Goodwin and Johns, 1977). Many other functions for this protein, depending on its location and synergizing partners, have been successively discovered. HMGB1 is present
The HMGB1-receptor RAGE
RAGE is a multiligand transmembrane receptor composed of three extracellular immunoglobulin-like domains – one variable-like (V) and two constant-like (C1 and C2) parts – a single transmembrane helix, and a short (41 residues) cytoplasmic tail (Fig. 3), critical for signal transduction (Koch et al., 2010, Park et al., 2010, Borsi et al., 2012). Interactions between RAGE and its ligands are mapped to the V/C1 domain, with the amino-terminal V domain providing the major contribution (Dattilo et
HMGB1 antagonists interacting with RAGE
An efficient strategy to inhibit RAGE–HMGB-1 signaling is based on the use of HMGB1-antagonists. In particular, recombinant box A (the truncated N-terminal domain of HMGB1) efficiently interacts with RAGE, competing with the binding of the full-length protein, but does not activate the receptor, lacking the proinflammatory cytokine activity localized on the B box (Li et al., 2003) (Fig. 4). The A box, as specific antagonist of HMGB1, is thus considered a potential anti-inflammatory agent (
Conclusions and perspectives
HMGB1 contributes to the pathogenesis of several chronic inflammatory and autoimmune diseases, including sepsis, rheumatoid arthritis, atherosclerosis, chronic kidney disease, systemic lupus erythematosus (SLE), and cancer.
As far as sepsis is concerned, which is the most common cause of death in intensive care units, the syndrome is pathologically mediated by the release of various proinflammatory cytokines, such as the early mediator TNF and the late one HMGB1, from immune cells. Secreted
Dedication
In memory of Dr Silvano Fumero.
Conflict of interest
The authors declare that there are no potential conflicts of interest.
Acknowledgments
We acknowledge MIUR (PRIN protocol n. 2009J54YAP_002) and AIRC, Italian Association for Cancer Research (grant n. 11947) for the financial support.
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