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

• Published in: European journal of immunology Vol. 29; no. 1; pp. 168 - 179
• Main Authors: Nilsen, Ellen M., Johansen, Finn‐Eirik, Kvale, Dag, Krajci, Peter, Brandtzaeg, Per
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY‐VCH Verlag GmbH 01.01.1999
• Subjects: Base Sequence; Cell Line; Cycloheximide - pharmacology; Cytokine; Cytokines - pharmacology; Dichlororibofuranosylbenzimidazole - pharmacology; DNA Probes - genetics; 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; HLA class I; Humans; Interferon-gamma - pharmacology; Interleukin-4 - pharmacology; pIg receptor; Protein Synthesis Inhibitors - pharmacology; Recombinant Proteins; Regulation; RNA Polymerase II - antagonists & inhibitors; RNA, Messenger - genetics; RNA, Messenger - metabolism; Secretory component; Secretory Component - biosynthesis; Secretory Component - genetics; Transcriptional Activation; Tumor Necrosis Factor-alpha - pharmacology
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/(SICI)1521-4141(199901)29:01<168::AID-IMMU168>3.0.CO;2-8

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‐γ, TNF‐α and IL‐4 activate transcription of the SC gene. This activation was slow, suggesting mediation via newly synthesized protein factors. IFN‐γ and TNF‐α, 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‐γ or TNF‐α stimulation, whereas the SC transcription rate did not peak until after 20 – 36 h of IFN‐γ, TNF‐α 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‐κB p50 subunit after TNF‐α stimulation, and IFN‐stimulated response element after IFN‐γ stimulation (and weakly after TNF‐α). 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.