HMGB1 and its physiological and pathological roles.

HMGB1 has been formerly known for its intracellular function - as the intranuclear non-histone DNA binding protein, which contributes to stabilization of nucleosomes, mediation of DNA bending and is regarded to have an essential position in DNA repair. Lately, its participation in innate and specific immune responses has been revealed. Passively released from necrotic cells or actively produced by various cell types it acts as an alarmin and is responsible for production of pro-inflammaory cytokines. HMGB1 is able to interact with RAGE and TLRs, receptors that belong into family of pattern recognition receptors and are involved in activation of pathways leading to production of pro-inflammatory cytokines. Its key role has been revealed in mediation of sepsis and as it is released later than other pro-inflammatory cytokines it became known as a "late mediator of sepsis". HMGB1 also contributes to the development of atherosclerosis and autoimmune diseases, e.g. its association with immunopathogenesis of SLE and RA has been suggested. Beside its negative function, HMGB1 protein seems to be able to attract stem cells to the area of inflammation and thus promotes regeneration processes. This paradoxical function of HMGB1 protein has also been revealed in growth and spread of many types of tumours. HMGB1 represents a potential target in therapy of various disorders related to inflammation (Fig. 2, Ref. 137).