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TLR4-dependent activation of dendritic cells by an HMGB1-derived peptide adjuvant
University of Calif San Diego, CA 92093 USA .
University of Calif San Diego, CA 92093 USA .
University of Coll Ghent, Belgium .
University of Coll Ghent, Belgium .
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2014 (English)In: Journal of Translational Medicine, ISSN 1479-5876, Vol. 12, no 211Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
BioMed Central , 2014. Vol. 12, no 211
National Category
Clinical Medicine
URN: urn:nbn:se:liu:diva-110973DOI: 10.1186/1479-5876-12-211ISI: 000341208700002PubMedID: 25123824OAI: diva2:751995

Funding Agencies|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

Available from: 2014-10-02 Created: 2014-10-01 Last updated: 2014-10-22

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