TRAIL contributes to the apoptotic effect of 13-cis retinoic acid in human sebaceous gland cells.

BACKGROUND: The full mechanism of action of isotretinoin [13-cis retinoic acid (13-cis RA)] in treating acne is unknown. 13-cis RA induces key genes in sebocytes that are involved in apoptosis, including Tumor necrosis factor Related Apoptosis Inducing Ligand (TRAIL). OBJECTIVES: In this study, we investigated the role of 13-cis RA-induced TRAIL within SEB-1 sebocytes. METHODS: Using 13-cis RA and recombinant human TRAIL (rhTRAIL) protein, we assessed induction of TRAIL and apoptosis in SEB-1 sebocytes, normal keratinocytes and patient skin biopsies. RESULTS: Treatment with rhTRAIL protein increased TUNEL-positive staining in SEB-1 sebocytes. TRAIL siRNA significantly decreased the percentage of TUNEL-positive SEB-1 sebocytes in response to 13-cis RA treatment. Furthermore, TRAIL expression increased in the skin of patients with acne after 1 week of isotretinoin therapy compared with baseline. TRAIL expression localized within sebaceous glands. Unlike sebocytes, TRAIL protein expression was not increased in normal human epidermal keratinocytes in response to 13-cis RA, nor did rhTRAIL induce apoptosis in keratinocytes, suggesting that TRAIL is key in the sebocyte-specific apoptotic effects of 13-cis RA. CONCLUSIONS: Taken together, our data suggest that TRAIL, like the neutrophil gelatinase-associated lipocalin, is involved in mediating 13-cis RA apoptosis of sebocytes.

Isotretinoin increases skin-surface levels of neutrophil gelatinase-associated lipocalin in patients treated for severe acne.

BACKGROUND: A clear-cut need exists for safe and effective alternatives to the use of isotretinoin in severe acne. Lack of data regarding the specifics of isotretinoin's mechanism of action has hampered progress in this area. Recently, the protein neutrophil gelatinase-associated lipocalin (NGAL) has been identified as a mediator of the apoptotic effect of isotretinoin on sebocytes. OBJECTIVES: To establish further the clinical relevance of NGAL and to elucidate the factors that induce NGAL expression in sebocytes. METHODS: Methods were developed to isolate and quantify skin-surface levels of NGAL from normal subjects and patients with acne undergoing treatment with isotretinoin. RESULTS: Patients with acne were found to have higher skin levels of NGAL compared with normal subjects. Studies in SEB-1 sebocytes indicate that NGAL expression is increased in response to Propionibacterium acnes and interleukin (IL)-1ß. In patients, isotretinoin increases NGAL levels by 2·4-fold on the skin surface and this increase precedes decreases in sebum and P. acnes counts. CONCLUSIONS: These data support the hypothesis that NGAL is an important mediator of the early effects of isotretinoin on the sebaceous glands and provide insights into the mechanisms that regulate NGAL expression in the skin.