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LPS induces apoptosis in macrophages mostly through the autocrine production of TNF-alpha

J Xaus1, M Comalada, A F Valledor

  • 1Departament de Fisiologia (Biologia del Macròfag) and Fundació August Pi i Sunyer, Campus de Bellvitge, Facultat de Biologia Universitat de Barcelona, Barcelona, Spain.

Blood
|June 14, 2000
PubMed

Insights

Lipopolysaccharide (LPS) triggers macrophage apoptosis via two pathways: early cell death is driven by tumor necrosis factor (TNF) secretion, while later cell death involves nitric oxide (NO) production.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Medicine

Background:

  • Endotoxic shock, induced by lipopolysaccharide (LPS), involves significant tissue damage mediated by macrophages.
  • Tumor necrosis factor (TNF) and nitric oxide (NO) are key inflammatory mediators released by macrophages during endotoxic shock.

Purpose of the Study:

  • To elucidate the distinct mechanisms by which LPS induces apoptosis in bone marrow-derived macrophages (BMDM).
  • To differentiate the roles of TNF and NO in early versus late-phase LPS-induced macrophage apoptosis.

Main Methods:

  • Stimulation of BMDM with LPS and assessment of apoptosis over time.
  • Inhibition of inducible NO-synthase (iNOS) and use of iNOS-deficient mice.
  • Analysis of TNF-receptor deficient mice (p55 and p75).
  • Gene expression analysis for p53 and Bax.

Main Results:

  • LPS-induced apoptosis peaked at 6 hours, preceding significant NO production (12-24 hours).
  • Early apoptosis was primarily mediated by TNF, as evidenced by reduced cell death in TNF-receptor deficient macrophages.
  • Nitric oxide significantly contributed to late-phase apoptosis, correlating with p53 and Bax gene induction.

Conclusions:

  • LPS-induced macrophage apoptosis involves two independent pathways: early, TNF-dependent apoptosis and later, NO-dependent apoptosis.
  • TNF plays a predominant role in the initial phase of LPS-induced cell death.
  • NO contributes to macrophage demise in the later stages, particularly when TNF-receptor signaling is absent.

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