Retinoic acid metabolism in Barrett’s esophagus, duodenum and normal esophagus.
Alexandra Lind1,2, Leo Koenderman2, J.G. Kusters3, T. Konijn4, R. Mebius4, Peter D.
Siersema1
Introduction: An increased numbers of immune cells can be found in Barrett’s esophagus
(BE). These cells are at least in part attracted by a homeostatic homing mechanism normally
operational in gut tissue. Retinoic acid (RA) is known to play a key role in homeostatic
homing of gut immune cells. We therefore examined the RA-pathway in patients with BE and
compared it with esophageal and duodenal tissue from patients with reflux esophagitis (RE)
and controls.
Aims: To investigate the expression of the RA pathway in esophageal biopsies from patients
with BE, BE, and controls and to compare this with findings in duodenal tissue.
Materials and methods: mRNA was obtained from biopsies of esophageal columnar
epithelium, squamous epithelium and duodenum of BE patients (n=10), inflamed squamous
epithelium, normal squamous epithelium and duodenum of RE patients (n=8) and squamous
epithelium (n=12) and duodenum of controls (n=5). RALDH1-3 (RA producing enzymes),
RAR-β (RA-receptor), CYP26A1 (RA-catabolizing enzyme), dendritic cell markers (CD1a,
CD1c, CD123 (IL-3 receptor, marker for plasmacytoid cells)), CD11c, CD83, DC-sign), were
amplified by real-time PCR. We performed hierarchical clustering using OmniViz®
(BioChipNetTM, Düsseldorf, Germany).
Results: Expression of RALDH1 was not different between tissue from Barrett segment and
all duodenal tissues, but was significantly higher than in all squamous esophageal tissues.
Expression of RALDH2 and RAR-β was elevated in BE tissue compared to duodenal and
squamous esophageal tissue. There was a significant correlation (r=0.6, p<0.05) between
expression of RALDH2 and CD123 in BE tissue, whereas CD123 did not correlate with
expression of CD83. DC-sign was highly expressed in duodenal tissues, whereas CD1a and
CD1c expressions were higher in squamous esophageal biopsies. The expression of
CYP26A1 was higher in inflamed squamous esophageal epithelium of RE patients than in BE
tissue (p=0.02). Hierarchical clustering of the results resulted in a distinctive separation
between duodenal and BE biopsies vs. squamous esophageal biopsies. Expression of IFN-γ
and IL-4 was not elevated in BE compared to the other groups.
Conclusion: We found evidence that both the RA-pathway and homing receptors in BE tissue
have more similarities with duodenal tissue than squamous esophageal epithelium. As it is
known that RALDH2 is typically expressed in dendritic cells, the correlation between
RALDH2- and CD123-positive (dendritic) cells suggests that plasmacytoid dendritic cells are
the source of the RA pathway in BE tissue. As RA is an agent with anti-cancer and antiinflammatory functions, it may play a protective role in the development of esophageal
adenocarcinoma in BE.