Lipopolysaccharide-induced interleukin-10 in mice: role of endogenous tumor necrosis factor-alpha

Eur J Immunol. 1995 Oct;25(10):2888-93. doi: 10.1002/eji.1830251027.


Interleukin (IL)-10 is known to protect mice against the lethal effects of lipopolysaccharides (LPS) and is considered to be an anti-inflammatory cytokine which suppresses the production of pro-inflammatory cytokines. We have examined the interactions of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) with IL-10. Neutralization of TNF-alpha in murine bone marrow-derived macrophages resulted in a significant reduction of LPS-inducible IL-10 production. In mice, injection of 5 mg/kg LPS induced circulating IL-10 with a biphasic time course exhibiting an early peak 1.5 h after challenge (synchronous with TNF-alpha) and, after a nadir at 6 h, a second increase between 8 and 12 h. Treatment of mice with neutralizing anti-mouse TNF-alpha antiserum significantly increased LPS-induced IL-10 plasma levels between 1.5 and 6 h but diminished those at 12 h, while circulating IL-6, interferon-gamma (IFN-gamma) and granulocyte colony-stimulating factor (G-CSF) concentrations were attenuated overall, without a biphasic response. Analysis of LPS-induced IL-10 mRNA expression in different tissues 1 h and 8 h after LPS or LPS plus anti-TNF-alpha revealed that the amount of transcripts in the liver correlated with circulating early and late IL-10 levels. Our findings suggest that endogenous TNF-alpha down-regulates the early and up-regulates the late LPS-induced IL-10 synthesis in vivo and that the liver is the major source of circulating IL-10 after stimulation with LPS.

MeSH terms

  • Animals
  • Bacterial Toxins / pharmacology
  • Bone Marrow Cells
  • Cells, Cultured
  • Endotoxins / pharmacology
  • Female
  • Gene Expression Regulation / drug effects*
  • Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology
  • Immunologic Deficiency Syndromes / immunology
  • Immunologic Deficiency Syndromes / physiopathology
  • Interferon-gamma / biosynthesis
  • Interleukin-10 / biosynthesis*
  • Interleukin-10 / genetics
  • Lipopolysaccharides / pharmacology*
  • Macrophages / drug effects*
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Mice, SCID
  • Organ Specificity
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / physiology*


  • Bacterial Toxins
  • Endotoxins
  • Lipopolysaccharides
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • salmonella toxin
  • Interleukin-10
  • Interferon-gamma
  • Granulocyte-Macrophage Colony-Stimulating Factor