Isotretinoin Revisited: Pluripotent Effects on Human Sebaceous Gland Cells

Nelson et al. confirmed the previously described antiproliferative effect of isotretinoin on human sebocytes. They attributed a portion of this decrease to cell cycle arrest and detected sebocyte apoptosis, which was not recapitulated by alitretinoin or tretinoin. These events were specific to sebocytes, as isotretinoin failed to induce apoptosis in keratinocytes. Isotretinoin-induced apoptosis was shown to be an RAR-independent mechanism

Sebaceous-immunobiology is orchestrated by sebum lipids

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Chloracne: From clinic to research

AbstractChloracne is the most sensitive and specific marker for a possible dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin) intoxication. It is clinically characterized by multiple acneiform comedone-like cystic eruptions mainly involving face in the malar, temporal, mandibular, auricular/retroauricular regions, and the genitalia, often occurring in age groups not typical for acne vulgaris. Histopathology is essential for a definite diagnosis, which exhibits atrophy or absence of sebaceous glands as well as infundibular dilatation or cystic formation of hair follicles, hyperplasia of epidermis, and hyperpigmentation of stratum corneum. The appearance of chloracne and its clinical severity does not correlate with the blood levels of dioxins. Pathogenesis of chloracne remains largely unclear. An “aryl hydrocarbon receptor”-mediated signaling pathway affecting the multipotent stem cells in the pilosebaceous units is probably the major molecular mechanism inducing chloracne. Chloracne is resistant to all the available treatment modalities used to treat acne. The aim of treatment is to lower or to eliminate the accumulated dioxins in the body at the very beginning of intoxication, e.g., by using dioxin-chelating substances such as synthetic dietary fat substitutes. The problem of dioxin contamination and its potential health hazards should be taken seriously in the wave of industrial globalization in the twenty-first century. Clinicians, especially dermatologists, are in the forefront of early diagnosis of dioxin intoxication

Altered Proliferation, Synthetic Activity, and Differentiation of Cultured Human sebocytes in the Absence of Vitamin A and Their Modulation by Synthetic Retinoids

Human sebocytes maintained in medium containing delipidized serum were studied for ultrastructural characteristics, cell proliferation, lipid synthesis, immunophenotype, and keratin expression before and after the addition of the synthetic retinoids isotretinoin and acitretin (10-8 - 10-5 M).Compared to the properties of sebocytes cultured in normal sebocyte medium (1–2 × 10-7 M vitamin A), the use of delipidized serum (undetectable amounts of vitamin A) resulted in prominent decrease of i) proliferation; ii) number of intracellular lipid droplets and synthesis of total lipids, especially triglycerides, squalene, and wax esters; and iii) labeling with monoclonal antibodies identifying progressive and late-stage sebocyte differentiation. Intercellular spaces narrowed and cell-to-cell contacts were established by abundant desmosomes. Lanosterol was induced. Keratins 14, 16, 17, and 18 were upregulated and the keratin 16: keratin 4 ratio, negatively correlating with sebocyte differentiation, increased.Addition of isotretinoin and acitretin exerted a biphasic effect. At concentrations ≤ 10-7 M, both compounds enhanced sebocyte proliferation and synthesis of total lipids, especially triglycerides and cholesterol, and decreased Ianosterol, keratin 16, and the keratin 16: keratin 4 ratio. In contrast, retinoid concentrations > 10-7 M inhibited sebocyte proliferation in a dose-dependent manner.Our findings indicate that vitamin A is essential for proliferation, synthetic activity, and differentiation of human sebocytes in vitro. Synthetic retinoids partially reinstate the altered functions of sebocytes maintained in medium containing delipidized serum. In contrast to the previously shown isotretinoin-specific response of cultured sebocytes in the presence of vitamin A, similar effects of isotretinoin and acitretin were obtained in its absence. This suggests different interactions of synthetic retinoids with vitamin A, possibly influencing their efficacy on the sebacceous gland

Cutibacterium acnes phylotype I and II strains interact differently with human skin cells

Acne vulgaris is one of the most common skin disorders and affects the pilosebaceous units. Although the exact pathogenesis of acne is still unknown, Cutibacterium acnes (formerly known as Propionibacterium acnes) is considered one of the key contributing factors. In fact, a significant association exists between C. acnes strains belonging to phylotype I and acne. However, there is still heavy debate on the exact role of C. acnes in acne and its behavior in the pilosebaceous unit, and more specifically its interactions with the human skin cells. In this study, key elements of the host-pathogen interaction were studied for a collection of C. acnes strains, belonging to phylotype I and II, including association with HaCaT keratinocytes and SZ95 sebocytes, the effect of C. acnes on keratinocyte tight junctions in a HaCaT monoculture and in an additional keratinocyte-sebocyte co-culture model, and C. acnes invasion through the keratinocyte cell layer. Our data showed association of all C. acnes strains to both skin cell lines, with a significantly higher association of type I strains compared to type II strains. Microscopic imaging and western blot analysis of the tight junction protein ZO-1, together with transepithelial electrical resistance (TEER) measurements revealed an initial induction of keratinocyte tight junctions after 24 h infection but a degradation after 48 h, demonstrating a decline in cell lining integrity during infection. Subsequently, C. acnes was able to invade after 48 h of infection, although invasion frequency was significantly higher for type II strains compared to type I strains

A practical guide for the study of human and murine sebaceous glands in situ

The skin of most mammals is characterised by the presence of sebaceous glands (SGs), whose predominant constituent cell population is sebocytes, that is, lipid-producing epithelial cells, which develop from the hair follicle. Besides holocrine sebum production (which contributes 90% of skin surface lipids), multiple additional SG functions have emerged. These range from antimicrobial peptide production and immunomodulation, via lipid and hormone synthesis/metabolism, to the provision of an epithelial progenitor cell reservoir. Therefore, in addition to its involvement in common skin diseases (e.g. acne vulgaris), the unfolding diversity of SG functions, both in skin health and disease, has raised interest in this integral component of the pilosebaceous unit. This practical guide provides an introduction to SG biology and to relevant SG histochemical and immunohistochemical techniques, with emphasis placed on in situ evaluation methods that can be easily employed. We propose a range of simple, established markers, which are particularly instructive when addressing specific SG research questions in the two most commonly investigated species in SG research, humans and mice. To facilitate the development of reproducible analysis techniques for the in situ evaluation of SGs, this methods review concludes by suggesting quantitative (immuno-)histomorphometric methods for standardised SG evaluation

Expression of Lipogenic Factors Galectin-12, Resistin, SREBP-1, and SCD in Human Sebaceous Glands and Cultured Sebocytes

The transcription factors CCAAT enhancer-binding protein α, β, and δ, and peroxisome proliferator-activated receptor γ are known to be crucial to the differentiation of adipocytes and are expressed in sebaceous gland cells. As lipogenesis is key to both adipocyte and sebocyte differentiation we hypothesize that sebocytes follow a similar program of differentiation to adipocytes. We have investigated the expression of known adipogenic factors resistin, galectin-12, sterol response –element-binding protein–1 (SREBP-1) and stearoyl-CoA desaturase in the immortalized sebaceous gland cell line SZ95 and whole skin. Reverse transcriptase-PCR analysis showed the expression of galectin-12, resistin, SREBP-1, and stearoyl-CoA desaturase mRNAs in SZ95 sebocytes. Immunoreactivity was observed for galectin-12 and SREBP-1 in the nuclei and resistin in the cytoplasm of basal sebocytes, and stearoyl CoA desaturase in the cytoplasm of basal and luminal sebocytes of human scalp skin. Expression of galectin-12, resistin, and SREBP-1 in SZ95 sebocytes was confirmed by Western blot analysis. These data provide further evidence that pathways of differentiation in adipocytes and sebocytes could be similar and therefore further understanding of sebaceous gland differentiation and lipogenesis and potential therapies for sebaceous gland disorders may be obtained from our knowledge of adipocyte differentiation

Beyond acne: current aspects of sebaceous gland biology and function

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A retinoic acid-inducible skin-specific gene (RIS-1/psoriasin): molecular cloning and analysis of gene expression in human skin in vivo and cultured skin cells in vitro

A retinoic acid (RA) inducible skin-specific gene transcript (RIS-1) was isolated by differential hybridization screening of a RA-treated human skin cDNA library. The library was constructed from pooled RNA derived from normal adult human skin treated with all trans -RA for 4 h (n=6) and 12 h (n=6) in vivo . RIS-1 cDNA corresponded to a 0.6 kb transcript that was barely detectable in normal adult human skin but was significantly induced by 8 h in RA-treated compared to vehicle-treated skin (range 1.1–3.6 fold). Prolonged RA treatment for up to 24 h further increased relative RIS-1 mRNA levels by 1.3–5.5 fold. HPLC analysis of the RA content of 0.1% RA-treated skin in vivo revealed significant levels at 6 h (18.8–120.6 ng RA/g wet weight tissue; approximately 240 nM), immediately preceding the time point at which the increased RIS-1 mRNA level was first seen. This concentration of RA also induced the mRNA levels for cellular RA binding protein II (1.6–19 fold), a marker of RA activity in human skin. RIS-1 mRNA was detected by Northern and dot blotting only in normal skin but not in any other normal human tissues examined, indicating a tissue-specific pattern of gene expression. RIS-1 transcripts were detected at very low levels in untreated cultured human epidermal keratinocytes, while no expression was seen in dermal fibroblasts and melanocytes, the other major cell types in skin. Southern analysis of human and mouse DNA indicated the existence of evolutionarily conserved sequences for RIS-1 between these two species. The polypeptide sequence derived from the partial RIS-1 cDNA was found to be identical to the calcium binding domain found in ‘psoriasin’, a gene whose expression appears to be increased in the skin of psoriasis patients.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43250/1/11033_2004_Article_BF00996356.pd