IL-4, IL-10 and IFN-gamma have distinct, but interacting, effects on differentiation-induced changes in TNF-alpha and TNF receptor release by cultured human monocytes

Cytokine. 1996 Jan;8(1):49-57. doi: 10.1006/cyto.1996.0007.


Monocytes cultured in vitro differentiate to a macrophage-like phenotype and undergo functional changes, including reduced capacity for release of TNF-alpha and the soluble p55 receptor for TNF (sTNF-R55) but enhanced capacity for release of the soluble p75 receptor (sTNF-R75). The cytokines IL-4 and IL-10 act on monocytes to suppress the release of pro-inflammatory cytokines, including TNF-alpha, and to influence the release of sTNF-R. We therefore investigated the influence of differentiation over 15 days in vitro on the spontaneous and LPS- and IFN-gamma-induced release of TNF-alpha and sTNF-R from human monocytes and examined the actions of IL-4 and IL-10 on these. Unstimulated monocytes did not release TNF-alpha at any stage but released progressively larger amounts of sTNF-R75 with time. LPS-stimulated release of TNF-alpha declined substantially after the first day and was consistently suppressed by IL-10 and IL-4 but increased by IFN-gamma. Monocytes cultured with IL-10 released more sTNF-R75 at all times and expressed more mRNA for TNF-R75 at day 8. LPS stimulation consistently enhanced both spontaneous and IL-10-augmented release of sTNF-R75, whilst IFN-gamma co-stimulation consistently suppressed them. The influence of IL-4 on sTNF-R75 release, however, depended qualitatively on both the length of time in culture and on conditions of stimulation. The effects of LPS and IFN-gamma on TNF-alpha and sTNF-R75 release were progressively lost with increasing time in culture in the presence of IL-4. sTNF-R55 was not detectable after the first day of culture under any of these conditions. IL-4, IL-10 and IFN-gamma therefore have distinct, but interacting, effects on the balance between TNF-alpha and sTNF-R75 release by maturing monocytes. These interactions may be relevant to the pathogenesis or treatment of TNF-alpha-mediated diseases, where sTNF-R may act to neutralize or stabilise TNF, thereby modifying biological activity.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Blotting, Northern
  • Cell Differentiation
  • Cell Survival / drug effects
  • Cells, Cultured
  • Drug Interactions
  • Flow Cytometry
  • Gene Expression / drug effects
  • Humans
  • Interferon-gamma / pharmacology*
  • Interleukin-10 / pharmacology*
  • Interleukin-4 / pharmacology*
  • Kinetics
  • Lipopolysaccharides / pharmacology
  • Macrophages / cytology
  • Monocytes / cytology*
  • Monocytes / drug effects
  • Monocytes / physiology*
  • Receptors, Tumor Necrosis Factor / biosynthesis*
  • Time Factors
  • Tumor Necrosis Factor-alpha / biosynthesis*


  • Lipopolysaccharides
  • Receptors, Tumor Necrosis Factor
  • Tumor Necrosis Factor-alpha
  • Interleukin-10
  • Interleukin-4
  • Interferon-gamma