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HMGB1 Develops Enhanced Proinflammatory Activity by Binding to Cytokines¹

Department of Medicine, University of Alabama, Birmingham, AL 35294

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-1β, IFN-, or TNF-. 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-1β, IFN-, and TNF- had enhanced proinflammatory activity, resulting in increased production of MIP-2 and TNF- by exposed cells. IL-1β was bound to HMGB1 isolated from cells cultured with this cytokine, and purified HMGB1 incubated with recombinant IL-1β acquired proinflammatory activity. Addition of anti-IL-1β Abs or the IL-1 receptor antagonist to cell cultures blocked the proinflammatory activity of HMGB1 purified from IL-1β-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-1β.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by National Institutes of Health Grants GM049222, HL062221, and HL076206.

² Address correspondence and reprint requests to Dr. Edward Abraham, Department of Medicine, University of Alabama, Boshell Diabetes Building 420, 1530 3rd Avenue South, Birmingham, AL 35294. E-mail address: eabraham{at}uab.edu

³ Abbreviations used in this paper: HMGB1, high mobility group box protein 1; HA, hemagglutinin; IL-1Ra, IL-1R antagonist.

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