Aryl hydrocarbon receptor-dependent inhibition of AP-1 activity by 2,3,7,8-tetrachlorodibenzo-p-dioxin in activated B cells

Toxicol Appl Pharmacol. 2002 Jun 1;181(2):116-23. doi: 10.1006/taap.2002.9403.


B cells have been identified as sensitive cellular targets responsible for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-mediated suppression of humoral immunity. In previous studies, TCDD was shown to produce a significant inhibition of IgM secretion and mu gene expression in LPS-activated CH12.LX B cells (AhR expressing) but not in BCL-1 B cells (AhR deficient). The present studies extend these previous findings by investigating the effect of TCDD on AP-1 and nuclear factor (NF)-kappaB, both of which play an important role in B-cell activation, differentiation, and immunoglobulin (Ig) gene expression. Electrophoretic mobility shift assays and chloramphenicol acetyl transferase reporter gene experiments demonstrated that lipopolysaccharide (LPS)-induced DNA binding and transcriptional activity of AP-1 was markedly inhibited by TCDD at 24, 48, and 72 h after cellular activation of CH12.LX cells. Conversely, TCDD treatment produced no significant change on the activity of NF-kappaB. Two AhR antagonists, alpha-naphthoflavone and 2,2',5,5'-tetrachlorobiphenyl, attenuated TCDD-induced inhibition of AP-1 binding in CH12.LX cells. Concordant with this result, TCDD did not inhibit LPS-induced AP-1 activity in BCL-1 B cells. Moreover, supershift analysis revealed the major component of the AP-1 complex in LPS-activated CH12.LX cells was c-Jun. Additional studies revealed that the nuclear c-jun and c-jun steady-state mRNA expression was inhibited by TCDD treatment. Collectively, these results suggest that TCDD-induced inhibition of IgM expression by B cells may be mediated, at least in part, through a down-regulation of AP-1 activity in an AhR-dependent manner.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism*
  • Benzoflavones / pharmacology
  • Chloramphenicol O-Acetyltransferase / genetics
  • Chloramphenicol O-Acetyltransferase / metabolism
  • Environmental Pollutants / toxicity*
  • Genes, Reporter / drug effects
  • Lipopolysaccharides / pharmacology
  • Lymphocyte Activation / immunology
  • Lymphoma
  • Mice
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism
  • Polychlorinated Biphenyls / pharmacology
  • Polychlorinated Dibenzodioxins / pharmacology*
  • Proto-Oncogene Proteins c-jun / genetics
  • Proto-Oncogene Proteins c-jun / metabolism
  • RNA, Messenger / metabolism
  • RNA, Neoplasm / analysis
  • Receptors, Aryl Hydrocarbon / deficiency
  • Receptors, Aryl Hydrocarbon / immunology
  • Receptors, Aryl Hydrocarbon / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription Factor AP-1 / antagonists & inhibitors
  • Transcription Factor AP-1 / metabolism*
  • Tumor Cells, Cultured


  • Benzoflavones
  • Environmental Pollutants
  • Lipopolysaccharides
  • NF-kappa B
  • Polychlorinated Dibenzodioxins
  • Proto-Oncogene Proteins c-jun
  • RNA, Messenger
  • RNA, Neoplasm
  • Receptors, Aryl Hydrocarbon
  • Transcription Factor AP-1
  • 2,5,2',5'-tetrachlorobiphenyl
  • alpha-naphthoflavone
  • Polychlorinated Biphenyls
  • Chloramphenicol O-Acetyltransferase