Negative regulation of two hyperproliferative keratinocyte differentiation markers by a retinoic acid receptor-specific retinoid: insight into the mechanism of retinoid action in psoriasis.
Retinoids down-regulate the expression of metalloproteinases, cytokines, and other genes involved in cell proliferation and inflammation. Tazarotene (AGN 190168), a retinoic acid receptor (RAR)-specific retinoid, is effective in the treatment of psoriasis, a hyperproliferative and inflammatory skin disease. Because negative regulation of genes appears to be important in the antiproliferative and antiinflammatory action of retinoids, we studied the down-regulation of genes in skin raft cultures by this antipsoriatic retinoid. By subtraction hybridization, we found that migration inhibitory factor-related protein (MRP-8) and skin-derived anti-leukoproteinase (SKALP) are down-regulated by AGN 190168. MRP-8 and SKALP are overexpressed in psoriatic lesions as compared to the normal epidermis, and they are markers of hyperproliferative keratinocyte differentiation. We also show that MRP-8 expression is retinoid inhibitable in cultured keratinocytes induced to differentiate with 10% serum or IFN-gamma, and that MRP-8 is inhibited by RAR but not by retinoid X receptor-specific retinoids in a dose-dependent manner. Finally, MRP-8, SKALP, and the previously characterized differentiation marker, transglutaminase I, are all down-regulated in vivo in psoriatic lesions after treatment with AGN 190168 in comparison to placebo. Taken together, these data suggest that these markers may be down-regulated by tazarotene in psoriasis through direct action on keratinocyte gene expression rather than by an overall tazarotene effect on lesional therapeutic status.
Nagpal
S
S
Department of Biology, Allergan Inc., Irvine, California 92713, USA.
Thacher
S M
SM
Patel
S
S
Friant
S
S
Malhotra
M
M
Shafer
J
J
Krasinski
G
G
Asano
A T
AT
Teng
M
M
Duvic
M
M
Chandraratna
R A
RA
D000943:Antigens, Differentiation / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology; D015415:Biomarkers; D002135:Calcium-Binding Proteins / Q000235:genetics; D040501:Calgranulin A; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology; D018076:DNA, Complementary / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D006004:Glycogen Debranching Enzyme System / Q000235:genetics; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D015603:Keratinocytes / Q000737:chemistry / Q000166:cytology* / Q000201:enzymology; D008297:Male; D009539:Nicotinic Acids / Q000494:pharmacology; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins / Q000235:genetics; D011565:Psoriasis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D012176:Retinoids / Q000494:pharmacology; D012680:Sensitivity and Specificity; D015842:Serine Proteinase Inhibitors / Q000235:genetics; D012867:Skin / Q000166:cytology; D013723:Teratogens / Q000494:pharmacology
D000943:Antigens, Differentiation; D000970:Antineoplastic Agents; D015415:Biomarkers; D002135:Calcium-Binding Proteins; D040501:Calgranulin A; D018076:DNA, Complementary; D006004:Glycogen Debranching Enzyme System; D009539:Nicotinic Acids; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D012176:Retinoids; D015842:Serine Proteinase Inhibitors; D013723:Teratogens; C086827:tazarotene; D007371:Interferon-gamma; C020569:4 alpha-glucanotransferase