Prostaglandin E₂ and Krüppel-like transcription factors synergistically induce the expression of decay-accelerating factor in intestinal epithelial cells

Summary

The decay-accelerating factor (DAF) prevents the intestinal mucosa from bystander killing by complement. Prostaglandin E₂ (PGE₂) induces the expression of DAF that may protect the tumour environment from complement attack. In the present study, we demonstrate synergistic actions of PGE₂ and two Krüppel-like factors (KLFs), which are zinc finger-containing transcription factors, in DAF regulation. Overexpression of KLF4 and KLF5 robustly induced transcriptional activity of the DAF promoter. In combination, PGE₂ and either KLF4 or KLF5 increased the expression of DAF in a synergistic fashion. Moreover, cyclooxygenase (COX-1 and COX-2) enzymes, KLF4/5 and DAF protein were coordinately expressed in normal intestinal mucosa as well as in intestinal neoplasm. In radiation-injured mouse intestine, COX-1 was rapidly induced and remained at relatively high levels. While KLF5 was quickly elevated after irradiation, KLF4 exhibited a delayed increase. Interestingly, levels of DAF increased gradually following the induction of COX-1 and KLFs. Mimicking the circumstances in vivo, coexpression of both COX and KLFs resulted in a synergistic or additive induction of DAF transcription in intestinal epithelial cells. Our data suggest that COX-derived PGE₂ may collaborate with KLF4/5 to regulate the activation of the complement system and exert diverse effects on the intestinal epithelium.