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EMBO reports 3, 10, 995–1001 (2002)
doi:10.1093/embo-reports/kvf198
Published online: October 2002
The nuclear protein HMGB1 is secreted by monocytes via a non-classical, vesicle-mediated secretory pathway
Stefania Gardella1, Cristina Andrei1, Denise Ferrera1, Lavinia V. Lotti2, Maria R. Torrisi2, Marco E. Bianchi3 & Anna Rubartelli1
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1 National Cancer Research Institute, Largo Rosanna Benzi, 10, 16132 Genoa, Italy
2 Department of Experimental Medicine and Pathology, University of Roma 'La Sapienza', 00161 Rome, Italy
3 San Raffaele University and Scientific Institute San Raffaele, via Olgettina 58, 20132 Milan, Italy
To whom correspondence should be addressed
Anna Rubartelli Tel: +39 010 5600 799; Fax: +39 010 5600 264; anna.rubartelli@istge.it
Received 15 March 2002; Accepted 20 August 2002.
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Abstract
HMGB1, a non-histone nuclear factor, acts extracellularly as a mediator of delayed endotoxin lethality, which raises the question of how a nuclear protein can reach the extracellular space. We show that activation of monocytes results in the redistribution of HMGB1 from the nucleus to cytoplasmic organelles, which display ultrastructural features of endolysosomes. HMGB1 secretion is induced by stimuli triggering lysosome exocytosis. The early mediator of inflammation interleukin (IL)-1 is also secreted by monocytes through a non-classical pathway involving exocytosis of secretory lysosomes. However, in keeping with their respective role of early and late inflammatory factors, IL-1 and HMGB1 respond at different times to different stimuli: IL-1 secretion is induced earlier by ATP, autocrinally released by monocytes soon after activation; HMGB1 secretion is triggered by lysophosphatidylcholine, generated later in the inflammation site. Thus, in monocytes, non-classical secretion can occur through vescicle compartments that are at least partially distinct.
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