Modulation of Epidermal Terminal Differentiation in Patients after Long‐term Topical Corticosteroids

Sheu, Hamm Ming; Tai, Chang-Long; Kuo, Kou‐Wha; Yu, Hsin‐Su; Chai, Chee‐Yin

doi:10.1111/j.1346-8138.1991.tb03115.x

Cited by 36 publications

(25 citation statements)

References 41 publications

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“…However, 11β-HSD1 expression being limited to the supra-basal epidermal area seems reasonable, considering that 11β-HSD1-mediated suppression of excessive proliferation in differentiated keratinocytes might contribute to maintain adequate epidermal thickness. In addition to its known anti-inflammatory properties, glucocorticoid (e.g., cortisol and corticosterone) is known to regulate the proliferation of keratinocytes and prolong epidermal turnover time [22], [23], [24], [25]. Consistent with this, we have shown that selective inhibition of 11β-HSD1 promotes the proliferation of keratinocytes both in vitro and in vivo , suggesting that intracellular activators of cortisol would negatively regulate keratinocyte proliferation (Figure 3 and 5).…”

Section: Discussionsupporting

confidence: 76%

11β-Hydroxysteroid Dehydrogenase-1 Is a Novel Regulator of Skin Homeostasis and a Candidate Target for Promoting Tissue Repair

et al. 2011

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11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) catalyzes the interconversion of cortisone and cortisol within the endoplasmic reticulum. 11β-HSD1 is expressed widely, most notably in the liver, adipose tissue, and central nervous system. It has been studied intensely over the last 10 years because its activity is reported to be increased in visceral adipose tissue of obese people. Epidermal keratinocytes and dermal fibroblasts also express 11β-HSD1. However, the function of the enzymatic activity 11β-HSD1 in skin is not known. We found that 11β-HSD1 was expressed in human and murine epidermis, and this expression increased as keratinocytes differentiate. The expression of 11β-HSD1 by normal human epidermal keratinocytes (NHEKs) was increased by starvation or calcium-induced differentiation in vitro. A selective inhibitor of 11β-HSD1 promoted proliferation of NHEKs and normal human dermal fibroblasts, but did not alter the differentiation of NHEKs. Topical application of selective 11β-HSD1 inhibitor to the dorsal skin of hairless mice caused proliferation of keratinocytes. Taken together, these data suggest that 11β-HSD1 is involved in tissue remodeling of the skin. This hypothesis was further supported by the observation that topical application of the selective 11β-HSD1 inhibitor enhanced cutaneous wound healing in C57BL/6 mice and ob/ob mice. Collectively, we conclude that 11β-HSD1 is negatively regulating the proliferation of keratinocytes and fibroblasts, and cutaneous wound healing. Hence, 11β-HSD1 might maintain skin homeostasis by regulating the proliferation of keratinocytes and dermal fibroblasts. Thus 11β-HSD1 is a novel candidate target for the design of skin disease treatments.

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Section: Discussionsupporting

confidence: 76%

11β-Hydroxysteroid Dehydrogenase-1 Is a Novel Regulator of Skin Homeostasis and a Candidate Target for Promoting Tissue Repair

et al. 2011

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“…Additionally, the IPS-induced abnormalities in epidermal proliferation and differentiation are consistent with known effects of increased GC. Indeed, in the epidermis (Winter and Wilson, 1976;Sheu et al, 1991), the PS-induced abnormalities are mimicked by short-term topical and systemic GC treatment, which also decreased epidermal cell proliferation and thickness (Kao et al, 2003). Finally, the IPS-induced decrease in lipid synthesis and LB production could be GC mediated, since GC similarly inhibits these parameters (Kao et al, 2003), and topical treatment with exogenous lipids normalized both permeability barrier homeostasis and SC integrity in GC-treated animals, indicating a similarly important pathophysiologic role for GC in reduced lipid production (Kao et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…Prior work has shown that long-term GC treatment decreases epidermal proliferation and differentiation (Laurence and Christophers, 1976;du Vivier et al, 1982;Sheu et al, 1991;Sheu et al, 1997). But even short-term GC treatment inhibits epidermal lipid synthesis, resulting in decreased production and secretion of lamellar bodies (LB), and impaired production of lamellar membranes in the SC (Kao et al, 2003).…”

mentioning

confidence: 98%

Mechanisms by Which Psychologic Stress Alters Cutaneous Permeability Barrier Homeostasis and Stratum Corneum Integrity

Choi

Brown

Crumrine

et al. 2005

Journal of Investigative Dermatology

181

144

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Although many skin disorders, including psoriasis and atopic dermatitis, are adversely affected by psychologic stress (PS), the pathophysiologic link between PS and disease expression remains unclear. Recent studies demonstrated PS-induced alterations in permeability barrier homeostasis, mediated by increased endogenous glucocorticoids. Here, we assessed the mechanisms by which PS alters stratum corneum (SC) function. Insomniac psychologic stress (IPS) altered both barrier homeostasis and SC integrity. IPS decreased epidermal cell proliferation, impaired epidermal differentiation, and decreased the density and size of corneodesmosomes (CD), which was linked to degradation of CD proteins (e.g., desmoglein1). Barrier compromise was linked to decreased production and secretion of lamellar bodies (LB), which in turn could be attributed to a decrease in de novo synthesis of epidermal lipids. Topical physiologic lipids (equimolar cholesterol, ceramides, and free fatty acids) normalized both barrier homeostasis and SC integrity in IPS mice, further evidence that lipid deficiency accounted for these functional abnormalities. Thus, PS inhibition of epidermal lipid synthesis results in decreased LB formation and secretion, as well as decreased CD, compromising both permeability barrier homeostasis and SC integrity. These studies suggest that topical treatment with epidermal physiologic lipids could be beneficial in stress-induced, barrier-associated dermatoses, such as psoriasis and atopic dermatitis.

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“…Prolonged treatment with GC decreases epidermal proliferation and differentiation (9,26,32,33). Additionally, more recent studies by our laboratory demonstrated that GC treatment also impairs both permeability barrier homeostasis and SC integrity and cohesion (23).…”

mentioning

confidence: 99%

Glucocorticoid blockade reverses psychological stress-induced abnormalities in epidermal structure and function

Choi¹,

Demerjian²,

Crumrine³

et al. 2006

American Journal of Physiology-Regulatory, Integrative and Comp

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Recent studies have demonstrated that PS decreases epidermal proliferation and differentiation, impairs permeability barrier homeostasis, and decreases stratum corneum integrity. PS also increases the production of endogenous glucocorticoids (GC), and both systemic and topical GC cause adverse effects on epidermal structure and function similar to those observed with PS. We therefore hypothesized that increased endogenous GC in PS mediates its adverse cutaneous effects. To test this hypothesis, we used two independent approaches, administering either RU-486, a GC receptor antagonist that inhibits GC action, or antalarmin, a corticotropin-releasing hormone (CRH) receptor antagonist that prevents increased GC production in the face of PS. Inhibition of either GC action or production prevents the PS-induced decline in epidermal cell proliferation and differentiation, impairment in permeability barrier homeostasis, and decrease in stratum corneum (SC) integrity. Moreover, the pathophysiological basis for the abnormality in permeability barrier homeostasis; i.e., decreased lamellar body production and secretion, is restored toward normal by inhibition of GC action. Similarly, the mechanistic basis for the decrease in SC integrity, i.e., a reduction in corneodesmosomes, is also normalized by inhibition of GC action. Thus many of the adverse effects of PS on epidermal structure and function can be attributed to increased endogenous GC and conversely, approaches that either reduce GC production or action might benefit cutaneous disorders that are provoked or exacerbated by PS.RU-486; corticotropin-releasing hormone; stratum corneum integrity; barrier homeostasis PSYCHOLOGICAL STRESS (PS) is well recognized to provoke, exacerbate, or propagate many cutaneous dermatoses, including psoriasis and atopic dermatitis (20,31,35). Many of the disorders that are adversely affected by PS are also associated with abnormal permeability barrier function (17, 18). Studies in both rodents and human have demonstrated that PS perturbs permeability barrier homeostasis. While basal permeability barrier function is normal, the kinetics of barrier recovery following acute barrier disruption are delayed (2,7,8,16). This delay in barrier recovery is accounted for by a decrease in the production and secretion of lamellar bodies (LB) (5) with a resultant decrease in the formation of the extracellular lamellar membranes that mediate epidermal permeability barrier function (10). Epidermal lipid synthesis is essential for providing the lipids required for the formation of LB (11). Accordingly, the decrease in LB secretion in PS animals is explained by a decrease in epidermal lipid synthesis (5). Of note, the abnormality in barrier homeostasis induced by PS can be normalized by the topical applications of a mixture of barrier lipids, which normalize LB formation and secretion (5).In addition to adversely effecting barrier homeostasis, PS also decreases keratinocyte proliferation, impairs epidermal differentiation, and decreases stratum corneum (SC) ...

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Modulation of Epidermal Terminal Differentiation in Patients after Long‐term Topical Corticosteroids

Cited by 36 publications

References 41 publications

11β-Hydroxysteroid Dehydrogenase-1 Is a Novel Regulator of Skin Homeostasis and a Candidate Target for Promoting Tissue Repair

11β-Hydroxysteroid Dehydrogenase-1 Is a Novel Regulator of Skin Homeostasis and a Candidate Target for Promoting Tissue Repair

Mechanisms by Which Psychologic Stress Alters Cutaneous Permeability Barrier Homeostasis and Stratum Corneum Integrity

Glucocorticoid blockade reverses psychological stress-induced abnormalities in epidermal structure and function

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