title: The nuclear protein HMGB1 is secreted by monocytes via a non-classical, vesicle-mediated secretory pathway.
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)-1beta 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-1beta and HMGB1 respond at different times to different stimuli: IL-1beta 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.
authors.affiliation: National Cancer Research Institute, Genoa, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Gardella
authors.forename: Cristina
authors.initials: C
authors.lastname: Andrei
authors.forename: Denise
authors.initials: D
authors.lastname: Ferrera
authors.forename: Lavinia V
authors.initials: LV
authors.lastname: Lotti
authors.forename: Maria R
authors.initials: MR
authors.lastname: Torrisi
authors.forename: Marco E
authors.initials: ME
authors.lastname: Bianchi
authors.forename: Anna
authors.initials: A
authors.lastname: Rubartelli
mesh_terms: D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism* / Q000648:ultrastructure; D003593:Cytoplasm / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D024243:HMGB1 Protein / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation; D007700:Kinetics; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008070:Lipopolysaccharides / Q000737:chemistry; D008244:Lysophosphatidylcholines / Q000378:metabolism; D008856:Microscopy, Fluorescence; D016253:Microscopy, Immunoelectron; D009000:Monocytes / Q000378:metabolism*; D013347:Subcellular Fractions; D013997:Time Factors; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism
chemical_list: D024243:HMGB1 Protein; D008070:Lipopolysaccharides; D008244:Lysophosphatidylcholines; D007770:L-Lactate Dehydrogenase; D001619:beta-N-Acetylhexosaminidases