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

The transmembrane secretory component (SC, or pig receptor) plays a crucial role in mucosal immunity by translocating dimeric IgA and pentameric IgM t hrough exocrine epithelia. This receptor is up-regulated by cytokines in pa rallel with increased epithelial HLA expression. By use of the human epithe lial 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 mediati on 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 r un-on experiments showed that the transcription rate of HLA class I genes n early peaked after only 30 min of IFN-gamma or TNF-alpha stimulation, where as 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 d emonstrated binding of nuclear proteins from cytokine-stimulated HT-29 cell s to consensus elements in the promoter of the SC gene, involving the bindi ng site for the nuclear factor-kappa B p50 subunit after TNF-alpha stimulat ion, and IFN-stimulated response element after IFN-gamma stimulation (and w eakly after TNF-alpha). Our observations in vitro likely parallel events in vivo by which activated mucosal T cells and macrophages enhance pig recept or-mediated external transport of secretory IgA and IgM and up-regulate epi thelial HLA expression.