Neutrophil gelatinase–associated lipocalin mediates 13-cis retinoic acid–induced apoptosis of human sebaceous gland cells
Amanda M. Nelson, … , Wenlei Liu, Diane M. Thiboutot
Amanda M. Nelson, … , Wenlei Liu, Diane M. Thiboutot
Published March 3, 2008
Citation Information: J Clin Invest. 2008;118(4):1468-1478. https://doi.org/10.1172/JCI33869.
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Research Article Dermatology

Neutrophil gelatinase–associated lipocalin mediates 13-cis retinoic acid–induced apoptosis of human sebaceous gland cells

Abstract

13-cis retinoic acid (13-cis RA; also known as isotretinoin) is the most potent agent available for treatment of acne. It is known that the drug induces apoptosis in cells cultured from human sebaceous glands, but its mechanism of action has not been determined. In this study, skin biopsies were taken from 7 patients with acne prior to and at 1 week of treatment with 13-cis RA. TUNEL staining confirmed that 13-cis RA induced apoptosis in sebaceous glands. Transcriptional profiling of patient skin and cultured human sebaceous gland cells (SEB-1 sebocytes) indicated that lipocalin 2 was among the genes most highly upregulated by 13-cis RA. Lipocalin 2 encodes neutrophil gelatinase–associated lipocalin (NGAL), which functions in innate immune defense and induces apoptosis of murine B lymphocytes. Increased immunolocalization of NGAL was noted in patients’ sebaceous glands following treatment with 13-cis RA, and recombinant NGAL induced apoptosis in SEB-1 sebocytes. Furthermore, apoptosis in response to 13-cis RA was inhibited in the presence of siRNA to lipocalin 2. These data indicate that NGAL mediates the apoptotic effect of 13-cis RA and suggest that agents that selectively induce NGAL expression in sebaceous glands might represent therapeutic alternatives to the use of 13-cis RA to treat individuals with acne.

Authors

Amanda M. Nelson, Wei Zhao, Kathryn L. Gilliland, Andrea L. Zaenglein, Wenlei Liu, Diane M. Thiboutot

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Figure 2

QPCR verification of gene array changes.

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QPCR verification of gene array changes. In order to verify the directio...
In order to verify the direction and magnitude of the changes in gene expression induced by 13-cis RA in the gene microarrays, QPCR was performed using primers to select genes whose expression was significantly changed by 13-cis RA in the array analysis. (A) Comparison of array analysis and QPCR on RNA obtained from patient skin biopsies at baseline and 1 week of 13-cis RA treatment. Data represent the mean ± SEM of the fold change in gene expression as determined by QPCR in 5 subjects compared to array analysis performed in 6 subjects. RARRES1, retinoic acid receptor responder 1; S100A7, psoriasin; SERPINA3, serine proteinase inhibitor A3; PLA2G7, phospholipase A2 group 7. (B) Comparison of array analysis and QPCR on RNA obtained from SEB-1 sebocytes incubated for 72 hours in the presence or absence of 13-cis RA. Data represent the mean ± SEM of the fold change in gene expression as determined by QPCR in 8 samples compared to array analysis performed in 3 samples. QPCR results were analyzed by REST-XL software program and *P < 0.05 was considered significant. IGFBP3, insulin-like growth factor–binding protein 3; GATA3, GATA-binding protein 3; ZBTB16, zinc finger and BTB domain-containing 16.