Modulation of IL-12 p35 and p40 promoter activity by smokeless tobacco extract is associated with an effect upon activation of NF-κB but not IRF transcription factors

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15 Scopus citations

Abstract

Interleukin (IL)-12 (p70), composed of p35 and p40 subunits, stimulates cellular immunity and inflammation. Stimulation of IL-12 production by smokeless tobacco extract (STE) could increase the chances of oral inflammatory disease. However, p40 forms homodimers and is part of IL-23 heterodimers. Expression of p35 and p40 in response to lipopolysaccharide (LPS) and interferon (IFN)-γ requires activation of nuclear factor-kappa-B (NF-κB) and interferon regulatory factor (IRF) transcription factors. To determine the impact of STE on expression of p35 and p40, the activities of p35 and p40 promoter reporter plasmids in RAW264.7 cells stimulated with STE alone or in the presence of IFN-γ and LPS were assessed. In addition, nuclear localizations of NF-κB p50, p65 and IRF-1, -2 and -8 in RAW264.7 cells treated with STE were evaluated. The results show that STE alone stimulates p40 and p35 promoter activity and enhances IFN-γ-induced p40 and p35 promoter activity. In contrast, STE had no effect on LPS-induced p35 and p40 promoter activity and diminished IFN-γ/LPS-induced p35 promoter activity. STE had little effect upon nuclear localization of IRFs, but it stimulated nuclear localization of both NF-κB p50 and p65. STE also stimulated IFN-γ-induced activation of NF-κB p50 but reduced nuclear localization of IFN-γ- and IFN-γ/LPS-induced NF-κB p65. SN50, an inhibitor of NF-κB nuclear localization, significantly lowered STE-induced p35 and p40 promoter activity. These results suggest that STE stimulation of bioactive IL-12 production is correlated with its impact upon both p35 and p40 and can be attributed in part through an effect upon NF-κB p50 nuclear localization.

Original languageEnglish (US)
Pages (from-to)735-745
Number of pages11
JournalInternational Immunopharmacology
Volume3
Issue number5
DOIs
StatePublished - May 2003

Keywords

  • IL-12
  • Macrophages
  • NF-κB
  • Tobacco

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Pharmacology

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