title: Retinoic acid inhibits interleukin-4-induced eotaxin production in a human bronchial epithelial cell line.
abstract: 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, which are members of the nuclear receptor family. We investigated whether RA can alter expression of eotaxin, a potent eosinophil chemoattractant that is regulated by the transcription factors signal transducer and activator of transcription 6 (STAT6) and NF-kappaB. 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 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 TNF-alpha-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.
authors.affiliation: 1st Dept. of Medicine, Hokkaido Univ. School of Medicine, North 15, West 7, Kita-ku, Sapporo 060-8638, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Takamura
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Nasuhara
authors.forename: Motoko
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Tomoko
authors.initials: T
authors.lastname: Betsuyaku
authors.forename: Yoko
authors.initials: Y
authors.lastname: Tanino
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kinoshita
authors.forename: Etsuro
authors.initials: E
authors.lastname: Yamaguchi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Matsukura
authors.forename: Robert P
authors.initials: RP
authors.lastname: Schleimer
authors.forename: Masaharu
authors.initials: M
authors.lastname: Nishimura
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000077556:Alitretinoin; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001980:Bronchi / Q000166:cytology*; D002460:Cell Line; D054413:Chemokine CCL11; D018932:Chemokine CCL2 / Q000378:metabolism; D019742:Chemokines, CC / Q000235:genetics*; D004847:Epithelial Cells / Q000187:drug effects* / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000032:analysis; D050800:STAT6 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; C515456:CCL11 protein, human; D054413:Chemokine CCL11; D018932:Chemokine CCL2; D019742:Chemokines, CC; D012333:RNA, Messenger; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D000077556:Alitretinoin; D015847:Interleukin-4; D014212:Tretinoin