Submitted on August 26, 2003
Accepted on December 3, 2003
RETINOIC ACID INHIBITS INTERLEUKIN-4-INDUCED EOTAXIN PRODUCTION IN A HUMAN BRONCHIAL EPITHELIAL CELL LINE
Kei Takamura1, Yasuyuki Nasuhara1*, Motoko Kobayashi1, Tomoko Betsuyaku1, Yoko Tanino1, Ichiro Kinoshita1, Etsuro Yamaguchi1, Satoshi Matsukura2, Robert P. Schleimer3, and Masaharu Nishimura1
1 First Department of Medicine, Hokkaido University School of Medicine, Sapporo, Japan
2 First Depatment of Internal Medicine, Showa University, Tokyo, Japan
3 Division of Allergy and Clinical Immunology, Johns Hopkins Asthma and Allergy Center, Baltimore, MD, USA
* To whom correspondence should be addressed. E-mail: nasuhara{at}med.hokudai.ac.jp.
Retinoic acid (RA) is known to accelerate wound healing and induce cell differentiation. All-trans-RA (ATRA) exerts its effect by binding retinoic acid receptors (RARs), members of the nuclear receptor family. We investigated whether RA can alter expression of eotaxin, a potent eosinophil chemoattractant which is regulated by the transcription factors, signal transducer and activator of transcription 6 (STAT6) and nuclear factor-
B. We examined the effects of RA on eotaxin expression in a human bronchial
epithelial cell line BEAS-2B. ATRA and its stereodimer 9-cis retinoic acid (9-cis RA) inhibited interleukin-4 (IL-4)-induced release of eotaxin at 10-6 M by 78.0% and 52.0%, respectively (P<0.05). ATRA and 9-cis RA also significantly inhibited IL-4-induced eotaxin mRNA expression at 10-6 M by 52.3% and 53.5%, respectively (P<0.05). In contrast, neither ATRA nor 9-cis RA had any effects on tumor necrosis factor-
-induced eotaxin production. In transfection studies using eotaxin promoter luciferase plasmids, the inhibitory effect of ATRA on IL-4-induced eotaxin production was confirmed at the transcriptional level. Interestingly, ATRA had no effects on IL-4-induced tyrosine phosphorylation, nuclear
translocation, or DNA binding activity of STAT6. Activating protein-1 was not involved in ATRA-mediated transrepression of eotaxin with IL-4 stimulation. The mechanism of the
inhibitory effect of ATRA on IL-4-induced eotaxin production in human bronchial epithelial cells has not been elucidated but does not appear to be due to an effect on STAT6 activation. These findings raise the possibility that RA may reduce eosinophilic airway inflammation, one of the prominent pathological features of allergic diseases such as bronchial asthma.
