HMGB1 develops enhanced proinflammatory activity by binding to cytokines.
High mobility group box 1 protein (HMGB1), originally characterized as a nuclear DNA-binding protein, has also been described to have an extracellular role when it is involved in cellular activation and proinflammatory responses. In this study, FLAG-tagged HMGB1 was inducibly expressed in the presence of culture media with or without added IL-1beta, IFN-gamma, or TNF-alpha. HMGB1 purified from cells grown in culture media alone only minimally increased cytokine production by MH-S macrophages and had no effect on murine neutrophils. In contrast, HMGB1 isolated from cells cultured in the presence of IL-1beta, IFN-gamma, and TNF-alpha had enhanced proinflammatory activity, resulting in increased production of MIP-2 and TNF-alpha by exposed cells. IL-1beta was bound to HMGB1 isolated from cells cultured with this cytokine, and purified HMGB1 incubated with recombinant IL-1beta acquired proinflammatory activity. Addition of anti-IL-1beta Abs or the IL-1 receptor antagonist to cell cultures blocked the proinflammatory activity of HMGB1 purified from IL-1beta-exposed cells, indicating that such activity was dependent on interaction with the IL-1 receptor. These results demonstrate that HMGB1 acquires proinflammatory activity through binding to proinflammatory mediators, such as IL-1beta.
Sha
Yonggang
Y
Department of Medicine, University of Alabama, 1530 3rd Avenue South, Birmingham, AL 35294, USA.
Zmijewski
Jaroslaw
J
Xu
Zhiwei
Z
Abraham
Edward
E
D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism*; D024243:HMGB1 Protein / Q000096:biosynthesis / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D006801:Humans; D018836:Inflammation Mediators / Q000302:isolation & purification / Q000378:metabolism* / Q000502:physiology; D008262:Macrophage Activation / Q000276:immunology; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018375:Neutrophil Activation / Q000276:immunology; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009842:Oligopeptides; D010455:Peptides / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology
D016207:Cytokines; D024243:HMGB1 Protein; D018836:Inflammation Mediators; D009842:Oligopeptides; D010455:Peptides; C085706:FLAG peptide