HMGB1 develops enhanced binding to cytokines
HMGB1 develops enhanced binding to cytokines
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DOI：
10.4049/jimmunol.180.4.2531
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发表时间：
2008-02-15
影响因子：
4.4
通讯作者：
Abraham, Edward
中科院分区：
文献类型：
--
作者：
Sha, Yonggang;Zmijewski, Jaroslaw;Abraham, Edward
高迁移率族蛋白I（HMGB 1）最初被表征为核DNA结合蛋白，当其参与细胞活化和促炎反应时也被描述为具有细胞外作用。在这项研究中，FLAG标记的HMGB 1在有或没有添加IL-1 β、IFN-γ或TNF-α的培养基存在下诱导表达。从单独在培养基中生长的细胞中纯化的HMGB 1仅最低限度地增加MH-S巨噬细胞的细胞因子产生，并且对鼠嗜中性粒细胞没有影响。相反，从IL-1 β、IFN-γ和TNF-α存在下培养的细胞中分离的HMGB 1具有增强的促炎活性，导致暴露的细胞产生MIP-2和TNF-α增加。IL-1 β与从用该细胞因子培养的细胞中分离的HMGB 1结合，并且用重组IL-1 β孵育的纯化的HMGB 1获得促炎活性。向细胞培养物中加入抗IL-1 β抗体或IL-1受体拮抗剂可阻断从IL-1 β暴露细胞中纯化的HMGB 1的促炎活性，表明这种活性依赖于与IL-1受体的相互作用。这些结果表明，HMGB 1通过与促炎介质如IL-1 β结合而获得促炎活性。
High mobility group box I 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-1 beta, 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-1 beta, IFN-gamma, and TNF-alpha had enhanced proinflammatory activity, resulting in increased production of MIP-2 and TNF-alpha by exposed cells. IL-1 beta was bound to HMGB1 isolated from cells cultured with this cytokine, and purified HMGB1 incubated with recombinant IL-1 beta acquired proinflammatory activity. Addition of anti-IL-1 beta Abs or the IL-1 receptor antagonist to cell cultures blocked the proinflammatory activity of HMGB1 purified from IL-1 beta-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-1 beta.