Smokeless tobacco extract decreases IL-12 production from LPS-stimulated but increases IL-12 from IFN-gamma-stimulated macrophages

Int Immunopharmacol. 2002 Feb;2(2-3):345-55. doi: 10.1016/s1567-5769(01)00160-6.


Modulation of IFN-gamma production from T cells by smokeless tobacco extract (STE) could be a factor in periodontal disease. The major inducer of IFN-gamma from T cells is bioactive IL-12 (p70), a heterodimeric protein composed of p35 and p40 subunits, while homodimeric IL-12 p40 antagonizes bioactive IL-12. Both p70 and p40 are produced by macrophages in response to lipopolysaccharide (LPS), IFN-gamma and/or CD40 ligation. To determine the impact of STE on IL-12 p40, p70 and IFN-gamma, splenic T cells were stimulated with anti-CD3 while splenic macrophages were stimulated with LPS in the presence or absence of STE. Production of IL-12 p40 and p70 from LPS-stimulated splenic macrophages and IL-12 p40, p70 and IFN-gamma from LPS/anti-CD3-stimulated T cells and macrophages was decreased by STE. To determine the impact of STE on macrophage IL-12 production alone, splenic or peritoneal macrophages were enriched and then stimulated. STE significantly diminished production of IL-12 p40 and p70 from LPS-stimulated peritoneal macrophages, LPS/IFN-gamma-stimulated peritoneal and splenic macrophages, but increased production of IL-12 p40 and p70 from IFN-gamma/CD40-stimulated splenic macrophages or IFN-gamma-stimulated peritoneal macrophages. None of the effects of STE on IL-12 was due to nicotine, rutin or chlorogenic acid. In contrast to STE, nicotine at 100 microg/ml significantly elevated production of IL-12 p40 and p70 from splenic macrophages stimulate by IFN-gamma/LPS. The results indicate that STE has a significant overall effect upon IL-12 production. It suppresses p40 and p70 production during responses to LPS or LPS/IFN-gamma but augments p40 and p70 production during responses to IFN-gamma without LPS. This affect could have a major impact on diseases associated with excessive production of IL-12.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chlorogenic Acid / pharmacology
  • Down-Regulation / drug effects
  • Down-Regulation / immunology
  • Female
  • Interferon-gamma / antagonists & inhibitors
  • Interferon-gamma / biosynthesis*
  • Interferon-gamma / pharmacology*
  • Interleukin-12 / antagonists & inhibitors*
  • Interleukin-12 / biosynthesis*
  • Interleukin-6 / biosynthesis
  • Lipopolysaccharides / pharmacology*
  • Macrophages / drug effects
  • Macrophages / immunology*
  • Macrophages / metabolism
  • Macrophages, Peritoneal / drug effects
  • Macrophages, Peritoneal / immunology
  • Macrophages, Peritoneal / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Nicotine / pharmacology
  • Plant Extracts / pharmacology
  • Rutin / pharmacology
  • Tobacco, Smokeless / pharmacology*
  • Up-Regulation / drug effects
  • Up-Regulation / immunology


  • Interleukin-6
  • Lipopolysaccharides
  • Plant Extracts
  • Interleukin-12
  • Chlorogenic Acid
  • Rutin
  • Nicotine
  • Interferon-gamma