title: High mobility group 1 protein (HMG-1) stimulates proinflammatory cytokine synthesis in human monocytes.
abstract: Lipopolysaccharide (LPS) is lethal to animals because it activates cytokine release, causing septic shock and tissue injury. Early proinflammatory cytokines (e.g., tumor necrosis factor [TNF] and interleukin [IL]-1) released within the first few hours of endotoxemia stimulate mediator cascades that persist for days and can lead to death. High mobility group 1 protein (HMG-1), a ubiquitous DNA-binding protein, was recently identified as a "late" mediator of endotoxin lethality. Anti-HMG-1 antibodies neutralized the delayed increase in serum HMG-1, and protected against endotoxin lethality, even when passive immunization was delayed until after the early cytokine response. Here we examined whether HMG-1 might stimulate cytokine synthesis in human peripheral blood mononuclear cell cultures. Addition of purified recombinant HMG-1 to human monocyte cultures significantly stimulated the release of TNF, IL-1alpha, IL-1beta, IL-1RA, IL-6, IL-8, macrophage inflammatory protein (MIP)-1alpha, and MIP-1beta; but not IL-10 or IL-12. HMG-1 concentrations that activated monocytes were within the pathological range previously observed in endotoxemic animals, and in serum obtained from septic patients. HMG-1 failed to stimulate cytokine release in lymphocytes, indicating that cellular stimulation was specific. Cytokine release after HMG-1 stimulation was delayed and biphasic compared with LPS stimulation. Computer-assisted image analysis demonstrated that peak intensity of HMG-1-induced cellular TNF staining was comparable to that observed after maximal stimulation with LPS. Administration of HMG-1 to Balb/c mice significantly increased serum TNF levels in vivo. Together, these results indicate that, like other cytokine mediators of endotoxin lethality (e.g., TNF and IL-1), extracellular HMG-1 is a regulator of monocyte proinflammatory cytokine synthesis.
authors.affiliation: Department of Medicine, Rheumatology Unit, Karolinska Hospital, 17176 Stockholm, Sweden. ulf@mbox313.swipnet.se
authors.forename: U
authors.initials: U
authors.lastname: Andersson
authors.forename: H
authors.initials: H
authors.lastname: Wang
authors.forename: K
authors.initials: K
authors.lastname: Palmblad
authors.forename: A C
authors.initials: AC
authors.lastname: Aveberger
authors.forename: O
authors.initials: O
authors.lastname: Bloom
authors.forename: H
authors.initials: H
authors.lastname: Erlandsson-Harris
authors.forename: A
authors.initials: A
authors.lastname: Janson
authors.forename: R
authors.initials: R
authors.lastname: Kokkola
authors.forename: M
authors.initials: M
authors.lastname: Zhang
authors.forename: H
authors.initials: H
authors.lastname: Yang
authors.forename: K J
authors.initials: KJ
authors.lastname: Tracey
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000494:pharmacology*; D002478:Cells, Cultured; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D016207:Cytokines / Q000096:biosynthesis*; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D024243:HMGB1 Protein; D006609:High Mobility Group Proteins / Q000235:genetics / Q000494:pharmacology*; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D016207:Cytokines; D024243:HMGB1 Protein; D006609:High Mobility Group Proteins; D007375:Interleukin-1; D015850:Interleukin-6; D016209:Interleukin-8; D008070:Lipopolysaccharides; D019402:Macrophage Inflammatory Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D018664:Interleukin-12