Transcription factors C/EBP-β and -δ regulate IL-6 production in IL-1β-stimulated human enterocytes

In recent studies, treatment with IL-1β of cultured Caco-2 cells, a human intestinal epithelial cell line, resulted in transcriptional upregulation of IL-6 production. The role of C/EBP-β and -δ in enterocyte IL-6 production is not known. Stimulation with IL-1β of Caco-2 cells transiently transfected with a luciferase reporter plasmid containing a wild-type IL-6 promoter resulted in an approximately 3.5-fold increase in luciferase activity. This effect of IL-1β was reduced by approximately 30% when the C/EBP binding site in the IL-6 promoter was mutated, supporting a role of C/EBP in the regulation of IL-6 production. When Caco-2 cells were treated with IL-1β in the presence of the MAPK inhibitor, PD-98059, IL-6 mRNA and protein levels were reduced by the same concentrations of PD-98059 that inhibited C/EBP DNA binding activity in previous studies. Finally, overexpression of C/EBP-β and -δ in IL-1β-treated Caco-2 cells resulted in a 10-12-fold increase in IL-6 production. The results suggest that the β and δ isoforms of the C/EBP family of transcription factors at least in part regulate IL-6 production in human intestinal epithelial cells.