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1. Sebacous Gland, development, function

2. Evaluation of human seobytes function and control, an in vitro model

3. Sebaceous gland increased secretion and its proinflammatory lipids a major factor in acne vulgaris

4. Comedogenesis is P. acnes independent and mediated by IL-1

Hautarzt. 2010;61(6):467-8

The sebaceous gland

Zouboulis CC
Abstract

The development and function of the sebaceous gland in the fetal and neonatal periods appear to be regulated by maternal androgens and by endogenous steroid synthesis, as well as by other morphogens. The most apparent function of the glands is to excrete sebum. A strong increase in sebum excretion occurs a few hours after birth; this peaks during the first week and slowly subsides thereafter. A new rise takes place at about age 9 years with adrenarche and continues up to age 17 years, when the adult level is reached. The sebaceous gland is a target organ but also an important formation site of hormones, and especially of active androgens. Hormonal activity is based on an hormone (ligand)-receptor interaction, whereas sebocytes express a wide spectrum of hormone receptors.

Androgens are well known for their effects on sebum excretion, whereas terminal sebocyte differentiation is assisted by peroxisome proliferator-activated receptor ligands. Estrogens, glucocorticoids, and prolactin also influence sebaceous gland function. In addition, stress-sensing cutaneous signals lead to the production and release of corticotrophin-releasing hormone from dermal nerves and sebocytes with subsequent dose-dependent regulation of sebaceous nonpolar lipids. Among other lipid fractions, sebaceous glands have been shown to synthesize considerable amounts of free fatty acids without exogenous influence. Atopic dermatitis, seborrheic dermatitis, psoriasis and acne vulgaris are some of the disease on which pathogenesis and severity sebaceous lipids may or are surely involved.

Dermatology. 1998;196(1):21-31.
The human sebocyte culture model provides new insights into development and management of seborrhoea and acne.

Zouboulis CC, Xia L, Akamatsu H, Setlmann H, Fritsch M, Hornemann S, Ruhl R, Chen W, Nau H, Orfanos CE.

Abstract

Seborrhoea and acne are exclusively human diseases and sebaceous gland differentiation is species specific. Therefore, fundamental research on human sebaceous cell function and control requires human in vitro models. The human sebocyte culture model, introduced in 1989, has been used in several studies to elucidate sebaceous gland activity and its regulation at the cellular level. Cultured human sebocytes have been shown to preserve important sebocytic characteristics, although they undergo an incomplete terminal differentiation in vitro. In vitro synthesis of free fatty acids without bacterial involvement and marked interleukin 1 alpha expression at the mRNA and protein levels with no further induction by lipopolysaccharides lead to the assumption that human sebocytes may initiate acne lesions by an intrinsic mechanism. Androgens affected sebocyte activity in vitro in a manner dependent on the localization of the sebaceous glands. In vitro stimulation of sebocyte proliferation by androgens could be completely abolished by spironolactone.

Cultured sebocytes strongly expressed type 1 5 alpha-reductase and metabolized testosterone to androstenedione, 5 alpha-androstanedione, 5 alpha-dihydrotestosterone, androsterone and 5 alpha-androstanediol, whereas the levels of 5 alpha-reductase activity were probably not feedback regulated. 4,7 beta-Dimethyl-4-aza-5 alpha-cholestan-3-one, a type 1 5 alpha-reductase inhibitor, induced an early, marked down-regulation of 5 alpha-reductase activity in human sebocytes in vitro, while hydrofinasteride, a type 2 inhibitor, required 10(3)-fold higher concentrations to induce similar effects. Stimulation of sebocyte proliferation by insulin, thyroid-stimulating hormone and hydrocortisone indicates that the hormonal control of the sebaceous gland could be a complex mechanism. Retinoids inhibited sebocyte proliferation in a dose-dependent manner and down-regulated lipid synthesis and sebocyte differentiation in vitro.

Isotretinoin was the most potent compound. On the other hand, vitamin A was found essential for sebocyte activity and differentiation in vitro and could be partially substituted by synthetic retinoids. The inhibitory effect of isotretinoin on sebocyte proliferation was barely affected by the presence of vitamin A. The low persistent isotretinoin levels or, more likely, the considerably elevated tretinoin concentrations detected in human sebocytes after treatment with isotretinoin in vitro may be responsible for the inhibitory effect of this compound on sebocyte activity.

Clin Dermatol. 2004 Sep-Oct;22(5):360-6.
Acne and sebaceous gland function.
Zouboulis CC.

Abstract
The embryologic development of the human sebaceous gland is closely related to the differentiation of the hair follicle and the epidermis. The number of sebaceous glands remains approximately the same throughout life, whereas their size tends to increase with age. The development and function of the sebaceous gland in the fetal and neonatal periods appear to be regulated by maternal androgens and by endogenous steroid synthesis, as well as by other morphogens. The most apparent function of the glands is to excrete sebum. A strong increase in sebum excretion occurs a few hours after birth; this peaks during the first week and slowly subsides thereafter. A new rise takes place at about age 9 years with adrenarche and continues up to age 17 years, when the adult level is reached. The sebaceous gland is an important formation site of active androgens.

Androgens are well known for their effects on sebum excretion, whereas terminal sebocyte differentiation is assisted by peroxisome proliferator-activated receptor ligands. Estrogens, glucocorticoids, and prolactin also influence sebaceous gland function. In addition, stress-sensing cutaneous signals lead to the production and release of corticotrophin-releasing hormone from dermal nerves and sebocytes with subsequent dose-dependent regulation of sebaceous nonpolar lipids. Among other lipid fractions, sebaceous glands have been shown to synthesize considerable amounts of free fatty acids without exogenous influence. Sebaceous lipids are responsible for the three-dimensional skin surface lipid organization. Contributing to the integrity of the skin barrier. They also exhibit strong innate antimicrobial activity, transport antioxidants to the skin surface, and express proinflammatory and anti-inflammatory properties. Acne in childhood has been suggested to be strongly associated with the development of severe acne during adolescence.

Increased sebum excretion is a major factor in the pathophysiology of acne vulgaris. Other sebaceous gland functions are also associated with the development of acne, including sebaceous proinflammatory lipids; different cytokines produced locally; periglandular peptides and neuropeptides, such as corticotrophin-releasing hormone, which is produced by sebocytes; and substance P, which is expressed in the nerve endings at the vicinity of healthy-looking glands of acne patients. Current data indicate that acne vulgaris may be a primary inflammatory disease. Future drugs developed to treat acne not only should reduce sebum production and Propionibacterium acnes populations, but also should be targeted to reduce proinflammatory lipids in sebum, down-regulate proinflammatory signals in the pilosebaceous unit, and inhibit leukotriene B(4)-induced accumulation of inflammatory cells. They should also influence peroxisome proliferator-activated receptor regulation. Isotretinoin is still the most active available drug for the treatment of severe acne.

Am J Clin Dermatol. 2000;1(4):201-209.

Is acne an infection of blocked pilosebaceous follicles? Implications for antimicrobial treatment

Eady EA, Cove JH.

Abstract

A model is proposed which is based on the assumption that acne is due to infection of functionally blocked pilosebaceous follicles by propionibacteria. Noninflamed lesions, which are first visible during the adrenarche in acne-prone individuals, do not contain propionibacteria. Comedogenesis appears to be independent of bacterial infection and may be driven by high levels of bioactive interleukin-1α derived from ductal hyperkeratinocytes. The stimulus which triggers interleukin-1α production is unknown. Formalin killed Propionibacterium acnes failed to stimulate production of the cytokine by cultured human keratinocytes in vitro.

Inflamed lesions are thought to arise from microcomedones, but the initiating events are unknown. Evidence that propionibacteria are involved in the generation of inflammatory lesions is inconclusive. The cellular infiltrate is consistent with a type IV hypersensitivity response to one or more persistent lesional antigens, not necessarily bacterial. The potent adjuvant activity of P. acnes would up-regulate the immune response to any antigen which came into contact with the mononuclear cell infiltrate.

Antibiotics are widely used in the treatment of acne, and their effects in selecting a predominantly resistant commensal population are well recognized. Although they reduce numbers of propionibacteria on the skin, other modes of action may contribute to or explain their therapeutic efficacy. At a time when there is global concern that antibiotic resistance rates in common bacterial pathogens may threaten our future ability to control bacterial infections, practices which promote the spread of antibiotic-resistant bacteria must be fully justified. A thorough reappraisal of the role of propionibacteria in acne is overdue. It is likely that further experimental work is needed to confirm or refute that P. acnes is aptly named.