High mobility group 1 protein (HMG-1) stimulates proinflammatory cytokine synthesis in human monocytes

J Exp Med. 2000 Aug 21;192(4):565-70. doi: 10.1084/jem.192.4.565.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / pharmacology*
  • Cells, Cultured
  • Chemokine CCL3
  • Chemokine CCL4
  • Cytokines / biosynthesis*
  • Enzyme-Linked Immunosorbent Assay
  • Fluorescent Antibody Technique
  • HMGB1 Protein
  • High Mobility Group Proteins / genetics
  • High Mobility Group Proteins / pharmacology*
  • Humans
  • Interleukin-1 / metabolism
  • Interleukin-10 / metabolism
  • Interleukin-12 / metabolism
  • Interleukin-6 / metabolism
  • Interleukin-8 / metabolism
  • Lipopolysaccharides / pharmacology
  • Macrophage Inflammatory Proteins / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Monocytes / drug effects
  • Monocytes / immunology*
  • Monocytes / metabolism
  • Phenotype
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Recombinant Proteins / pharmacology
  • Tumor Necrosis Factor-alpha / biosynthesis*
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism


  • Carrier Proteins
  • Chemokine CCL3
  • Chemokine CCL4
  • Cytokines
  • HMGB1 Protein
  • High Mobility Group Proteins
  • Interleukin-1
  • Interleukin-6
  • Interleukin-8
  • Lipopolysaccharides
  • Macrophage Inflammatory Proteins
  • RNA, Messenger
  • Recombinant Proteins
  • Tumor Necrosis Factor-alpha
  • Interleukin-10
  • Interleukin-12