title: Heat shock proteins and high mobility group box 1 protein lack cytokine function.
abstract: In search of the etiology and pathophysiology for autoimmune and chronic inflammatory diseases, many molecules have been identified as endogenous damage-associated molecules with proinflammatory cytokine functions that may be responsible for the sterile inflammation leading to tissue injuries observed in these disorders. HSPs and HMGB1 are intracellular molecular chaperones for peptides and DNAs, respectively. They are released extracellularly upon cellular injury or activation. In vitro studies revealed that HSPs and HMGB1 were capable of inducing the release of proinflammatory cytokines by monocytes and macrophages and the activation and maturation of DCs. These cytokine effects were reported to be mediated by TLR2 and TLR4 signal transduction pathways. Thus, they were called endogenous ligands of TLR2 and TLR4 and might serve as danger signals, alarmins, or damage-associated molecules to the host immune system. It has been suggested that HSPs provide a link between innate and adaptive immune systems, and HMGB1 functions at the cross-road between innate and adaptive immunity. However, recent evidence suggests that highly purified HSPs and HMGB1, although retaining their biological activities, do not have cytokine effects. Thus, HSPs and HMGB1 do not meet the definition of endogenous ligands of TLRs, danger signals, alarmins, or damage-associated molecules. In contrast, HSPs and HMGB1 are found to bind a number of pathogen-associated molecules, such as LPS and bacterial lipopeptides, and enhance the cytokine effects of these molecules. The significance of these cytokine-enhancing effects of HSPs and HMGB1 needs further investigation.
authors.affiliation: Research Service, Veterans Affairs Medical Center, Washington, DC, USA. min-fu.tsan2@va.gov
authors.forename: Min-Fu
authors.initials: MF
authors.lastname: Tsan
mesh_terms: D000818:Animals; D016207:Cytokines / Q000172:deficiency*; D024243:HMGB1 Protein / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans
chemical_list: D016207:Cytokines; D024243:HMGB1 Protein; D006360:Heat-Shock Proteins