High mobility group box 1 (HMGB 1): a new protein in the pathogenesis of ENT inflammatory and infectious diseases

High mobility group box 1 (HMGB 1): a new protein in the pathogenesis of ENT inflammatory and infectious diseases HMGB 1 una nuova proteina nella patogenesi della patologia infiammatoria ed infettiva ORL in addition to the well-known components of the immune response to inflammation, other inflammatory pathways have been recently invoked. Among these, an inflammatory molecule called high mobility group box 1 (hMgB1) can be highlighted, which is an evolutionary ancient protein that serves predominately as a DnA-binding protein with " alarmin " activity. yang et al. 1 used the term " alarmin " to indicate numerous granule-derived mediators that rapidly galvanize antigen-presenting cells (APCs) and trigger innate and adaptive immune responses. They represent the first host response to exogenous (infections) and endogenous (injuries) danger signals. Alarmins have the dual capacity to recruit and activate inflammatory cells including dendritic cells (DCs), using giα-protein-coupled receptor(s) (giPCr) and activating receptor(s), respectively. Alarmins are usually constitu-tively present in cells, such as leukocytes and epithelial cells, as components of the granules, cytoplasm and nucleus. They are endogenous peptides that are released in host defence against danger signals, and therefore, can be considered as a subset of damage associated molecular patterns (DAMPs) 1. hMgB1 is ubiquitously expressed in the nuclear compartment of eukaryotic cells functioning as a transcriptional regulator via interaction of its A-box and B-box subunits with DnA. Therefore, quiescent macrophages/monocytes constitutively express hMgB1 and maintain an intracellular " pool " of hMgB1 predominantly in the nucleus. in the late 1990's, Wang et al. 2 reported that extracellular hMgB1 is actively released as a late mediator of inflammation in sepsis by activated mac-rophages/monocytes. After stimulation with exogenous bacterial products such as endotoxin, or with endogenous pro-inflammatory cytokines such as TnF-α, il-1β and iFn-γ, cultures of macrophages, monocytes, and pitui-cytes actively release hMgB1 in a time-and dose-dependent manner. in addition to its active release, hMgB1 can also be released passively from necrotic or damaged cells. however, hMgB1 is not released by apoptotic cells, which degrade without setting off an inflammatory response. Therefore, hMgB1 is extracellularly released as a result of loss of membrane integrity upon necrosis of nucleated cells (including neutrophils) and by activated leukocytes via an initial acetylation on many of the 43 lysine residues of hMgB1 in the nucleus. As an extracel-lular protein, hMgB1 has pleomorphic effects including activation of nF-κB, diffuse endothelial activation, hepa-tocellulary injury, epithelial leak, and systemic activation of inflammatory …