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Bacterial endotoxin stimulates macrophages to release HMGB1 partly through CD14- and TNF-dependent mechanisms

Guoqian Chen1, Jianhua Li, Mahendar Ochani

  • 1Department of Emergency Medicine, North Shore University Hospital, New York University School of Medicine, 350 Community Drive, Manhasset, NY 11030, USA.

Journal of Leukocyte Biology
|August 28, 2004
PubMed

Insights

Bacterial lipopolysaccharide (LPS) triggers macrophages to release tumor necrosis factor (TNF) and high mobility group box 1 (HMGB1). HMGB1 release is partly dependent on CD14 and TNF, but not MAPK signaling pathways.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cellular Biology

Background:

  • Bacterial lipopolysaccharide (LPS) induces macrophages to release proinflammatory cytokines.
  • Tumor necrosis factor (TNF) is an early cytokine, while high mobility group box 1 (HMGB1) is a late cytokine.
  • CD14 and mitogen-activated protein kinases (MAPK) are known to be involved in LPS-induced TNF production, but their role in HMGB1 release is unclear.

Purpose of the Study:

  • To investigate the mechanisms underlying LPS-mediated HMGB1 release from macrophages.
  • To determine the involvement of CD14, MAPK signaling pathways, and TNF in HMGB1 release.

Main Methods:

  • Primary murine peritoneal macrophages were used.
  • Genetic disruption of CD14 and TNF expression.
  • Pharmacological inhibition of p38 and extracellular signal-regulated kinase (ERK)1/2 MAPK.
  • Treatment with neutralizing antibodies against TNF.
  • Treatment with spermine, an endogenous immunosuppressive molecule.

Main Results:

  • Genetic disruption of CD14 abrogated LPS-induced TNF production but only partially reduced HMGB1 release.
  • MAPK inhibitors (SB203580, SB202190, U0126, PD98059) attenuated TNF production but did not inhibit HMGB1 release.
  • Spermine significantly attenuated LPS-mediated HMGB1 release without affecting p38 MAPK activation.
  • Neutralizing TNF antibodies or genetic disruption of TNF partially reduced HMGB1 release at lower LPS concentrations.

Conclusions:

  • LPS stimulates macrophages to release HMGB1 through mechanisms partially dependent on CD14 and TNF.
  • MAPK signaling pathways are not essential for LPS-induced HMGB1 release.
  • HMGB1 release involves both CD14-dependent and -independent pathways, with a partial contribution from TNF.

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