Different regulatory pathways employed in cytokine-enhanced expression of secretory component and epithelial HLA class I genes

Eur J Immunol. 1999 Jan;29(1):168-79. doi: 10.1002/(SICI)1521-4141(199901)29:01<168::AID-IMMU168>3.0.CO;2-8.

Abstract

The transmembrane secretory component (SC, or pIg receptor) plays a crucial role in mucosal immunity by translocating dimeric IgA and pentameric IgM through exocrine epithelia. This receptor is up-regulated by cytokines in parallel with increased epithelial HLA expression. By use of the human epithelial cell line HT-29m3, we show that IFN-gamma, TNF-alpha and IL-4 activate transcription of the SC gene. This activation was slow, suggesting mediation via newly synthesized protein factors. IFN-gamma and TNF-alpha, but not IL-4, also up-regulated expression of HLA class I genes. However, this gene induction was rapid and did not depend on new protein synthesis. Nuclear run-on experiments showed that the transcription rate of HLA class I genes nearly peaked after only 30 min of IFN-gamma or TNF-alpha stimulation, whereas the SC transcription rate did not peak until after 20-36 h of IFN-gamma, TNF-alpha or IL-4 stimulation. Gel electrophoresis mobility shift assays demonstrated binding of nuclear proteins from cytokine-stimulated HT-29 cells to consensus elements in the promoter of the SC gene, involving the binding site for the nuclear factor-kappaB p50 subunit after TNF-alpha stimulation, and IFN-stimulated response element after IFN-gamma stimulation (and weakly after TNF-alpha. Our observations in vitro likely parallel events in vivo by which activated mucosal T cells and macrophages enhance pIg receptor-mediated external transport of secretory IgA and IgM and up-regulate epithelial HLA expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Cell Line
  • Cycloheximide / pharmacology
  • Cytokines / pharmacology*
  • DNA Probes / genetics
  • Dichlororibofuranosylbenzimidazole / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Epithelial Cells / drug effects
  • Epithelial Cells / immunology
  • Gene Expression Regulation / drug effects
  • Genes, MHC Class I / drug effects*
  • Histocompatibility Antigens Class I / biosynthesis*
  • Humans
  • Interferon-gamma / pharmacology
  • Interleukin-4 / pharmacology
  • Protein Synthesis Inhibitors / pharmacology
  • RNA Polymerase II / antagonists & inhibitors
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Recombinant Proteins
  • Secretory Component / biosynthesis*
  • Secretory Component / genetics*
  • Transcriptional Activation
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • Cytokines
  • DNA Probes
  • Enzyme Inhibitors
  • Histocompatibility Antigens Class I
  • Protein Synthesis Inhibitors
  • RNA, Messenger
  • Recombinant Proteins
  • Secretory Component
  • Tumor Necrosis Factor-alpha
  • Interleukin-4
  • Dichlororibofuranosylbenzimidazole
  • Interferon-gamma
  • Cycloheximide
  • RNA Polymerase II