The development of experimental models for the in vitro study of human sebaceous gland turned down the theory of a phylogenetic relict and led to the identification of several, unknown or disregarded functions of this organ. Such functions are the production of foetal vernix caseosa, the influence of three-dimensional organization of the skin surface lipids and the integrity of skin barrier and the influence on follicular differentiation. In addition, the sebaceous gland contributes to the transport of fat-soluble antioxidants from and to the skin surface, the natural photoprotection, the pro-and antiinflammatory skin properties and to the innate antimicrobial activity of the skin. It is mainly responsible for skin's independent endocrine function, the hormonally induced skin ageing process, the steroidogenic function of the skin as well as its thermoregulatory and repelling properties and for selective control of the hormonal and xenobiotical actions of the skin. Interestingly, sebocytes, at least in vitro, preserve characteristics of stem-like cells despite their programming for terminal differentiation. This review reports on various sebaceous gland functions, which are currently under investigation, including its role on the hypothalamus-pituitaryadrenal-like axis of the skin, the impact of acetylcholine on sebocyte biology, the activity of ectopeptidases as new targets to regulate sebocyte function, the effects of vitamin D on human sebocytes, the expression of retinoid metabolizing cytochrome P450 enzymes and the possible role of sebum as vehicle of fragrances. These multiple homeostatic functions award the sebaceous gland the role 'brain of the skin' and the most important cutaneous endocrine gland.

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Our method proved suitable for the detection of quantitative and qualitative changes in lipid profiles of both infundibulum cast content and surface lipids. It enabled simple, non-invasive and objective assessment of the most relevant lipid classes in the sebaceous infundibulum, and efficient monitoring of drug effects on the follicular infundibulum.

Acne is a chronic disease hallmarked by sebaceous hyperplasia, follicular hyperkeratosis, and inflammation. Parallel targeting of these factors is required to treat acne effectively. Inhibitors of dipeptidyl peptidase IV (DP IV) and aminopeptidase N (APN) show strong anti-inflammatory effects on immune cells and therapeutic efficacy in autoimmune disorders. Our investigation focused on the expression and functional relevance of these ectopeptidases in three cell types which exhibit an altered phenotype in early acne lesions. We showed for the first time expression of DP IV and APN on human sebocytes. In the SZ95 sebocyte cell line, the DP IV inhibitors Lys[Z(NO2)]-thiazolidide and Lys[Z(NO2)]-pyrrolidide and the APN inhibitors actinonin and bestatin suppressed proliferation, enhanced terminal differentiation, and slightly decreased total neutral lipid production. The anti-inflammatory and differentiation-restoring cytokine IL-1 receptor antagonist was significantly upregulated in SZ95 sebocytes and the HaCaT keratinocyte cell line in the presence of inhibitors. Furthermore, the inhibitors suppressed proliferation and IL-2 production of Propionibacterium acnes-stimulated T cells ex vivo and enhanced the expression of the immunosuppressive cytokine transforming growth factor-beta1. Our data provide first evidence for a functional role of DP IV and APN in the sebaceous gland apparatus and for their inhibitors, used alone or in combination, as completely new substances possibly affecting acne pathogenesis in a therapeutic manner.

The pathogenesis of acne, the most common skin disease, is complex and multifactorial. Clinical experience has demonstrated that parallel targeting of various pathogenetic factors, achieved either by mono- or combination therapy with appropriate drugs, represents the most effective approach to treating acne. Topical retinoids have been shown to expulse mature comedones, reduce microcomedone formation, and exert immunomodulatory effects. They have broad anti-acne activity without the risk of inducing bacterial resistance, which justifies their use as first-line treatment in most types of noninflammatory and inflammatory acne and makes them uniquely suitable as long-term medication to maintain remission after cessation of initial combination therapy. Systemic isotretinoin as a monotherapeutic agent strongly affects all four major pathogenetic factors and has been, in the hand of experienced dermatologists, a potent and safe agent for the treatment of severe and recalcitrant acne forms for more that 20 years. However, patient counseling, careful monitoring, and evaluation and management of adverse events are necessary. The use of isotretinoin has experienced a drawback now that its indication has been lowered from a first-line to a second-line medication.

SummaryTopical retinoids are important tools in the management of acne because they act against comedones and microcomedones and have direct anti-inflammatory effects. The substances approved for acne treatment comprise tretinoin (all-trans-retinoic acid), isotretinoin (13-cis retinoic acid) as well as the synthetic third-generation polyaromatic retinoids adapalene and tazarotene, the latter being approved for acne treatment in the US only. Retinaldehyde is used in cosmetic preparations against acne. All topical retinoids are effective as single agents in mild to moderate acne but differ in efficacy and tolerability. Tazarotene 0.1 % is more effective than tretinoin 0.025 % or 0.1 % microsphere gel or adapalene 0.1 % gel or cream (EBM-level 2c). Adapalene 0.1 % is equally effective to tretinoin 0.025 % or tretinoin microsphere 0.1 % gel or tretinoin 0.05 % cream or isotretinoin 0.05 % gel (EBM-level 2c). Adapalene 0.1 % gel is significantly better tolerated than tazarotene 0.1 % gel, tretinoin 0.025 % and tretinoin 0.05 % gel, tretinoin 0.05 % cream, tretinoin microsphere 0.1 % gel or isotretinoin 0.05 % gel (EBMlevel 2c). The safety profile of topical retinoids differs from their systemic counterparts and is related mainly to local adverse effects, such as erythema, dryness, itching and stinging. The currently available evidence justifies the use of topical retinoids in most types of acne and during maintenance treatment.

Suppression of collagen and matrix synthesis and inhibition of the fibrogenic cytokine transforming growth factor-beta(1) (TGF-beta(1)) is a major therapeutic goal in the treatment of fibrosis and keloids. Inhibitors of dipeptidyl peptidase IV (DP IV)-like activity affect cell growth and cytokine production and are currently under investigation for the treatment of metabolic, autoimmune and inflammatory diseases. We show here that the inhibitors of DP IV-like activity, Lys[Z(NO(2))]-thiazolidide and Lys[Z(NO(2))]-pyrrolidide, suppress proliferation in human skin fibroblasts and keloid-derived skin fibroblasts in vitro. They significantly decrease TGF-beta(1) expression and secretion of procollagen type I C-terminal peptide in supernatants of both cell types. Furthermore, they abrogate the TGF-beta(1)-induced stimulation of collagen synthesis, matrix deposition, and TGF-beta(1) and fibronectin expression. Both inhibitors lead to dephosphorylation of mitogen-activated protein kinases pp38 and pERK1/2, which are activated upon TGF-beta1 stimulation and have been implicated in fibrogenesis. In a mouse model of dermal fibrosis, induced by repetitive intracutaneous injections of TGF-beta(1), the profibrotic effect of TGF-beta(1) detected by dermal thickening, collagen I, and alpha-smooth muscle actin expression, is significantly suppressed in the presence of inhibitors. Inhibition of DP IV-like enzymatic activity may therefore represent a promising therapeutic approach for the treatment of fibrotic skin disorders and keloids.

Our data support the hypothesis that DP8 and/or DP9 represent additional pharmacological targets for the suppression of T cell proliferation and for anti-inflammatory therapy.