Negative regulation of two hyperproliferative keratinocyte differentiation markers by a retinoic acid receptor-specific retinoid: insight into the mechanism of retinoid action in psoriasis.

Abstract

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.

• Authors: S Nagpal, S M Thacher, S Patel, S Friant, M Malhotra, J Shafer, G Krasinski, A T Asano, M Teng, M Duvic, R A Chandraratna
• Journal: Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research (Cell Growth Differ) Vol. 7 Issue 12 Pg. 1783-91 (Dec 1996) ISSN: 1044-9523 [Print] United States
• PMID: 8959347 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antigens, Differentiation
• Antineoplastic Agents
• Biomarkers
• Calcium-Binding Proteins
• Calgranulin A
• DNA, Complementary
• Glycogen Debranching Enzyme System
• Nicotinic Acids
• Proteinase Inhibitory Proteins, Secretory
• Proteins
• RNA, Messenger
• Receptors, Retinoic Acid
• Retinoids
• Serine Proteinase Inhibitors
• Teratogens
• tazarotene
• Interferon-gamma
• 4 alpha-glucanotransferase

Topics

• Antigens, Differentiation (genetics)
• Antineoplastic Agents (pharmacology)
• Biomarkers
• Calcium-Binding Proteins (genetics)
• Calgranulin A
• Cell Differentiation (physiology)
• Cells, Cultured (chemistry, drug effects, enzymology)
• DNA, Complementary (genetics)
• Dose-Response Relationship, Drug
• Down-Regulation (physiology)
• Gene Expression Regulation, Enzymologic (drug effects, physiology)
• Glycogen Debranching Enzyme System (genetics)
• Humans
• Interferon-gamma (pharmacology)
• Keratinocytes (chemistry, cytology, enzymology)
• Male
• Nicotinic Acids (pharmacology)
• Proteinase Inhibitory Proteins, Secretory
• Proteins (genetics)
• Psoriasis (genetics, metabolism, pathology)
• RNA, Messenger (metabolism)
• Receptors, Retinoic Acid (genetics)
• Retinoids (pharmacology)
• Sensitivity and Specificity
• Serine Proteinase Inhibitors (genetics)
• Skin (cytology)
• Teratogens (pharmacology)