Abstract
High-mobility group box 1 protein (HMGB1), a member of highly conserved non-histone DNA binding protein family, has been studied as transcription factor and growth factor. Secreted extracellularly by activated monocytes and macrophages or passively released by necrotic or damaged cells, extracellular HMGB1 is a potent mediator of inflammation. Extracellular HMGB1 has apparently contrasting biological actions: it sustains inflammation (with the possible establishment of autoimmunity or of self-maintaining tissue damage), but it also activates and recruits stem cells, boosting tissue repair. Here, we focus on the role of HMGB1 in physiological and pathological responses, the mechanisms by which it contributes to tissue repair and therapeutic strategies base on targeting HMGB1.
Highlights
This Review article focuses on the biology of high-mobility group box 1 protein (HMGB1; known as amphoterin or HMG1), an evolutionarily ancient protein that was discovered recently to have a role as a cytokine
The pleiotropic functions exerted by extracellular High-mobility group box 1 protein (HMGB1) on specific target cells have been related to the ability of this protein to engage and activate different receptors, such as receptor for advanced glycation end products (RAGE) and toll-like receptors (TLRs) 2, 4 and 9 [42]
Since TLRs blockade does not completely abolish HMGB1 effect and HMGB1 can exert some of its biological activities at sub-nanomolar concentrations, the possibility that other not yet identified HMGB1 receptors exist is actual
Summary
This Review article focuses on the biology of high-mobility group box 1 protein (HMGB1; known as amphoterin or HMG1), an evolutionarily ancient protein that was discovered recently to have a role as a cytokine. A number of observations indicate that all cell types involved in tissue-repair mechanism are sensitive to extracellular HMGB1 and express functional HMGB1 receptors This cytokine-like protein acts as chemoattractant and pro-motogenic/pro-mitogenic stimulus for fibroblasts, keratinocytes, endothelial cells, vascular smooth muscle cells and vessel-associated stem cells (mesangioblast) [24±31]. In the B box is located a short 10 amino acid peptide (residues 130±139), produced by proteolytic processing of extracellular HMGB1, active in erythroleukaemia cell differentiation [38] This bioactive peptide is localized between the TLR4 and the RAGE bindLQJVLWHV LGHQWLILHG LQWKH% ER[RI+0*% DQGGRHVQ¶WRYHUODSZLWKWKHP7KH5$*( ELQGLQJ motif is located between residues 150-183, downstream from peptide 130±139, whereas the TLR4 binding site is a 20-mer peptide stretch containing C106, upstream from peptide 130-139 [19,20]. Reduced form, since recombinant HMGB1, supplemented with dithiothreitol (DTT), promotes cell migration, it is unable to induce TNF production [39]
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