期刊
JOURNAL OF TRANSLATIONAL MEDICINE
卷 12, 期 -, 页码 -出版社
BIOMED CENTRAL LTD
DOI: 10.1186/1479-5876-12-211
关键词
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资金
- National Institutes of Health/NCI [5U54 CA119335]
- U.S. Army Medical Research and Materiel Command [W81XWH-07-1-0412]
- Swedish Research Council [AI52731]
- Swedish Physicians against AIDS Research Foundation
- Swedish International Development Cooperation Agency
- SIDA SARC
- VINNMER for Vinnova
- Linkoping University Hospital Research Fund
- CALF
- Swedish Society of Medicine
High mobility group box protein 1 (HMGB1) acts as an endogenous danger molecule that is released from necrotic cells and activated macrophages. We have previously shown that peptide Hp91, whose sequence corresponds to an area within the B-Box domain of HMGB1, activates dendritic cells (DCs) and acts as an adjuvant in vivo. Here we investigated the underlying mechanisms of Hp91-mediated DC activation. Hp91-induced secretion of IL-6 was dependent on clathrin-and dynamin-driven endocytosis of Hp91 and mediated through a MyD88- and TLR4-dependent pathway involving p38 MAPK and NF kappa B. Endosomal TLR4 has been shown to activate the MyD88-independent interferon pathway. Hp91-induced activation of pIRF3 and IL-6 secretion was reduced in IFN alpha beta R knockout DCs, suggesting an amplification loop via the IFN alpha beta R. These findings elucidate the mechanisms by which Hp91 acts as immunostimulatory peptide and may serve as a guide for the future development of synthetic Th1-type peptide adjuvants for vaccines.
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