Retinoic acid receptor-nuclear factor-interleukin 6 antagonism. A novel mechanism of retinoid-dependent inhibition of a keratinocyte hyperproliferative differentiation marker.
Retinoids inhibit the expression of migration inhibitory factor-related protein-8 (MRP-8), a marker of hyperproliferative or abnormal keratinocyte differentiation, in a retinoic acid receptor (RAR)-dependent manner in various cell culture systems. MRP-8 expression is also down-regulated in vivo in psoriatic lesions after topical application of an anti-psoriatic RARbeta/gamma-selective synthetic retinoid, tazarotene. We demonstrate that an MRP-8 promoter linked to a chloramphenicol acetyltransferase reporter (MRP8CAT) faithfully replicates the differentiation-specific regulation of the endogenous keratinocyte MRP-8 gene. Further, interferon gamma and serum-induced expression of MRP8CAT is inhibited by retinoid receptors in a ligand-dependent manner. We also show that NF-IL6 acts as a transcriptional enhancer of MRP-8, and that RARs inhibit MRP8CAT by inhibiting the enhancer action of nuclear factor-interleukin-6 (NF-IL6). The NF-IL6 antagonism function of RAR is a complex of the core of the DNA binding domain and the hydrophobic zipper region. This manuscript identifies NF-IL6 as another transcription factor, in addition to AP1, whose activity is inhibited by RAR in a ligand-dependent manner. The interdiction of NF-IL6-dependent signal transduction pathway by RARs may explain some of the therapeutic effects of retinoids in inflammatory and proliferative diseases.
DiSepio
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D
Departments of Biology and Chemistry, Retinoid Research, Allergan Inc., Irvine, California 92612, USA.
Malhotra
M
M
Chandraratna
R A
RA
Nagpal
S
S
D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D051743:CCAAT-Enhancer-Binding Protein-delta; D022762:CCAAT-Enhancer-Binding Proteins; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D040501:Calgranulin A; D002454:Cell Differentiation; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics; D003001:Cloning, Molecular; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016350:Leucine Zippers; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000378:metabolism; D011401:Promoter Regions, Genetic; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*
D000943:Antigens, Differentiation; D022762:CCAAT-Enhancer-Binding Proteins; C497252:CEBPD protein, human; D002135:Calcium-Binding Proteins; D040501:Calgranulin A; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D009687:Nuclear Proteins; D016376:Oligonucleotides, Antisense; D018168:Receptors, Retinoic Acid; D014157:Transcription Factors; D051743:CCAAT-Enhancer-Binding Protein-delta; D007371:Interferon-gamma; D004247:DNA; D015500:Chloramphenicol O-Acetyltransferase