Differential expression of HPA axis homolog in the skin

Slominski, Andrzej; Wortsman, Jacobo; Tuckey, Robert C.; Paus, Ralf

doi:10.1016/j.mce.2006.12.012

Cited by 258 publications

(283 citation statements)

References 83 publications

(173 reference statements)

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“…Because P450scc is expressed in the gut where it plays a role in local corticosteroid production (FernandezMarcos et al, 2011), it could play a role in first-pass metabolism of ergosterol before it reaches the liver for excretion. Furthermore, P450scc is expressed in several other extra-adrenal and extragonadal tissues including skin, where it serves as a starting point for local steroids synthesis (Slominski et al, 2004(Slominski et al, , 2007, metabolizes 7-dehydrocholesterol (animal equivalent of plant ergosterol) , or potentially may play a role in nonclassic vitamin D metabolism (Slominski et al, 2005a(Slominski et al, , 2011. Thus, when topically applied, ergosterol may serve as a substrate for P450scc with potential implications in therapy of skin hyperproliferative or inflammatory disorders.…”

Section: Introductionmentioning

confidence: 99%

Human Cytochrome P450scc (CYP11A1) Catalyzes Epoxide Formation with Ergosterol

Tuckey¹,

Nguyen²,

Chen³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Cytochrome P450scc (P450scc) catalyzes the cleavage of the side chain of both cholesterol and the vitamin D 3 precursor, 7-dehydrocholesterol. The aim of this study was to test the ability of human P450scc to metabolize ergosterol, the vitamin D 2 precursor, and define the structure of the major products. P450scc incorporated into the bilayer of phospholipid vesicles converted ergosterol to two major and four minor products with a k cat of 53 mol ⅐ min

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Section: Introductionmentioning

confidence: 99%

Human Cytochrome P450scc (CYP11A1) Catalyzes Epoxide Formation with Ergosterol

Tuckey¹,

Nguyen²,

Chen³

et al. 2011

Drug Metab Dispos

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“…In addition, cholesterol, a precursor from which steroid hormones are synthesized, is produced by skin (31). All major components of HPA axis (CRH, CRH-R, urocortin, POMC, ACTH, MC-R) and critical enzymes necessary for GCs synthesis are produced and identified in skin (32)(33)(34)(35)(36). In addition, isolated hair follicles, dermal fibroblasts, and melanocytes secrete cortisol and display HPA axis-like regulatory feedback systems (37)(38)(39).…”

mentioning

confidence: 99%

Cortisol Synthesis in Epidermis Is Induced by IL-1 and Tissue Injury

Vukelic

Stojadinović

Pastar

et al. 2011

Journal of Biological Chemistry

176

196

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Glucocorticoids (GCs) are known inhibitors of wound healing. In this study we report the novel finding that both keratinocytes in vitro and epidermis in vivo synthesize cortisol and how this synthesis regulates wound healing. We show that epidermis expresses enzymes essential for cortisol synthesis, including steroid 11 ␤-hydroxylase (CYP11B1), and an enzyme that controls negative feedback mechanism, 11␤-hydroxysteroid dehydrogenase 2 (11␤HSD2). We also found that cortisol synthesis in keratinocytes and skin can be stimulated by ACTH and inhibited by metyrapone (CYP11B1 enzyme inhibitor). Interestingly, IL-1␤, the first epidermal signal of tissue injury, induces the expression of CYP11B1 and increases cortisol production by keratinocytes. Additionally, we found induction of CYP11B1 increased production of cortisol and activation of GR pathway during wound healing ex vivo and in vivo using human and porcine wound models, respectively. Conversely, inhibition of cortisol synthesis during wound healing increases IL-1␤ production, suggesting that cortisol synthesis in epidermis may serve as a local negative feedback to proinflammatory cytokines. Local GCs synthesis, therefore, may provide control of the initial proinflammatory response, preventing excessive inflammation upon tissue injury. Inhibition of GC synthesis accelerated wound closure in vivo, providing the evidence that modulation of cortisol synthesis in epidermis may be an important regulatory mechanism during wound healing.Acute wound healing is a complex biological process mediated by a network of signaling pathways that coordinate multiple cellular processes, including cellular migration and proliferation, ultimately leading to barrier restoration (1). Wound healing is a tightly spatiotemporally regulated process, and changes in any component of this process can be detrimental, leading to further tissue damage or impairment of healing (2, 3).For example, timing of inflammatory response is essential; proinflammatory signals are important in the early stage of healing, but they can be detrimental if they persist (4, 5), underscoring a need for tight control of both stimulators and inhibitors during the wound healing process.Upon injury, keratinocytes are the first cells that respond (6, 7) by releasing pre-stored interleukin-1 (IL-1) (8). IL-1 has an autocrine and a paracrine function; that is, to activate keratinocytes and to alert the surrounding cells and tissues. The release of IL-1 by keratinocytes, with subsequent release of additional signaling molecules (9, 10), demarcates the proinflammatory phase of wound healing. In response to these signals, activated keratinocytes start migrating and proliferating (7,8,11). Successful repair after tissue injury requires resolution of inflammatory response, transitioning keratinocyte (HEK) from activated to differentiating phenotype. However, very little is known about endogenous epidermal signals that control keratinocyte activation cycle and inflammatory response.Epidermal keratinocytes have important immunol...

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“…HF immune privilege, connective tissue sheath (CTS) mast cell degranulation. (see Arck et al, 2005a; Bodó et al, 2005 and2007; Botchkarev et al, 2004; Colombe et al., 2007; Deplewski and Rosenfield, 2000;Hasse et al, 2007; Kauser et al, 2006;Ohnemus et al, 2006;Paus et al, 2006;Peters et al, 2006b and2007;Philp et al, 2004;Slominski et al, 2007;Telek et al, 2007;Zouboulis et al, 2007) While this remains to be conclusively demonstrated, it is likely that HFeSC are fully integrated into this neuroendocrine tapestry of general HF biology. However, all we have to go by currently are some pointers to potentially important elements in the as yet obscure neuroendocrinology of HFeSC.…”

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confidence: 99%

“…It now needs to be characterized whether human and/or mouse HFeSC in the bulge express constitutively higher or lower levels of receptors for classical secreted stress mediators e.g. CRH, ACTH, NGF, substance P, prolactin and cortisol) -all of which are synthesized in the human HF itself (Peters et al, 2006 a;Slominski et al, 2007). Also, in view of the observation that these cells appear to fail to show appropriate desensitization responses to glucocorticoid stimulation (Chebotaev et al, 2007) one needs to know how HFeSC respond to stimulation with these neuron-endocrine stress mediators.…”

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confidence: 99%

(Neuro-)endocrinology of epithelial hair follicle stem cells

Paus

Arck

Tiede

2008

Molecular and Cellular Endocrinology

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The hair follicle is a repository of different types of somatic stem cells. However, even though the hair follicle is both a prominent target organ and a potent, non-classical site of production and/or metabolism of numerous polypetide-and steroid hormones, neuropeptides, neurotransmitters and neurotrophins, the (neuro-) endocrine controls of hair follicle epithelial stem cell (HFeSC) biology remain to be systematically explored.Focussing on HFeSCs, we attempt here to offer a "roadmap through terra incognita" by listing key open questions, by exploring endocrinologically relevant HFeSC gene profiling and mouse genomics data, and by sketching several clinically relevant pathways via which systemic and/or locally generated (neuro-)endocrine signals might impact on HFeSC. Exemplarily, we discuss e.g. the potential roles of glucocorticoid and vitamin D receptors, the hairless gene product, thymic hormones, bone morphogenic proteins (BMPs) and their antagonists, and Skg-3 in HFeSC biology. Furthermore, we elaborate on the potential role of nerve growth factor (NGF) and substance P-dependent neurogenic inflammation in HFeSC damage, and explore how neuroendocrine signals may influence the balance between maintenance and destruction of hair follicle immune privilege, which protects these stem cells and their progeny. These considerations call for a concerted research effort to dissect the (neuro)-endocrinology of HFeSCs much more systematically than before. The hair follicle (HF) and its special, associated mesenchyme (i.e. the connective tissue sheath, CTS) are repositories of different types of somatic stem cells (epithelial, mesenchymal, neural, mesenchymal) (Cotsarelis, 2006; Kruse et al., 2006;Millar, 2005;Ohyama et al., 2006;Tiede et al. 2007;Waters et al., 2007;Yu et al., 2006). These HFassociated stem cell populations are critical for HF development and function, including HF pigmentation (Nishimura et al., 2002(Nishimura et al., , 2005Sarin and Artandi, 2007). Fig. 1 shows several important, recognized hair follicle-associated stem cell populations and their bestcharacterized location(s) in the pilosebaceous unit, though it must be kept in mind that the indicated ones are unlikely to be the only stem cell population associated with mammalian skin appendages (Tiede et al. 2007). Clinical importance of hair follicle stem cellsHair follicle epithelial stem cells (HFeSCs) are clinically important, since they can be key targets for pathological processes, such as an autoaggressive inflammatory cell attack on HFeSC, e.g. in lupus erythematosus or lichen planopilaris, where the destruction of bulge HFeSCs (see Fig.1) abolishes the hair follicle's capacity to cycle and to rhythmically regenerate itself, leading to scarring alopecia (Cotsarelis, 2006;Hiroi et al., 2006;Mobini et al., 2005;Paus, 2006). Likewise, a gradual loss of HF melanocyte stem cells may exhaust the HF pigmentary unit's capacity to generate itself and to produce melanin and thus likely plays a key role in hair graying (Commo et al., 2004;...

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Differential expression of HPA axis homolog in the skin

Cited by 258 publications

References 83 publications

Human Cytochrome P450scc (CYP11A1) Catalyzes Epoxide Formation with Ergosterol

Human Cytochrome P450scc (CYP11A1) Catalyzes Epoxide Formation with Ergosterol

Cortisol Synthesis in Epidermis Is Induced by IL-1 and Tissue Injury

(Neuro-)endocrinology of epithelial hair follicle stem cells

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