Cortisol synthesis in epidermis is induced by IL-1 and tissue injury
Open accessAbstract
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 β-hydroxylase (CYP11B1), and an enzyme that controls negative feedback mechanism, 11β-hydroxysteroid dehydrogenase 2 (11βHSD2). We also found that cortisol synthesis in keratinocytes and skin can be stimulated by ACTH and inhibited by metyrapone (CYP11B1 enzyme inhibitor). Interestingly, IL-1β, 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-1β 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.
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Skin expresses 11βHSD2, which oxidizes cortisol to inactive cortisone.
“Skin also expresses 11βHSD2 which works in the oxidative direction, converting cortisol to the inactive cortisone [23, 64–66, 81].”
From Steroidogenesis in the skin: Implications for local immune functions (2013) · cites this paper as [65]
Dexamethasone treatment of human skin increased 11βHSD2 mRNA expression.
“In contrast, dexamethasone treatment of human skin was reported to increase 11βHSD2 expression at the mRNA level [65].”
From Steroidogenesis in the skin: Implications for local immune functions (2013) · cites this paper as [65]
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“Since porcine skin is often used for studies of skin wound healing (Lademann et al., 2011; Sullivan et al., 2001; Vukelic et al., 2011), using their corneas allows scientist to confirm that results obtained studying skin wounds are relevant to the cornea.”
BackgroundExtra-adrenal glucocorticoid biosynthesis: implications for autoimmune and inflammatory disorders
Slominski, R. M., Tuckey, R. C., Manna, P. R., Jetten, A. M., Postlethwaite, A., Raman, C., & Slominski, A. T. (2020) · Genes & Immunity · doi:10.1038/s41435-020-0096-6 · Cited by 155 · see citing works
Inflammation and immunity in organ regeneration
Mescher, A. L., Neff, A. W., & King, M. W. (2016) · Developmental & Comparative Immunology · doi:10.1016/j.dci.2016.02.015 · Cited by 145 · see citing works
“…synthesis) are now known to be wide-spread in cells of the skin and gastrointestinal tract, where they enhance immunoprotection and repair in these organs after exposure to pathogens or injury (Lin et al., 2014; Talaber et al., 2013; Vukelic et al., 2011; Zmijewski and Slominski, 2011).”
BackgroundAlmasian, A., Najafi, F., Eftekhari, M., Ardekani, M. R. S., Sharifzadeh, M. S., & Khanavi, M. (2020) · Materials Science and Engineering C · doi:10.1016/j.msec.2020.111039 · Cited by 139 · see citing works
Epidermal Differentiation in Barrier Maintenance and Wound Healing
Wikramanayake, T. C., Stojadinović, O., & Tomic‐Canic, M. (2014) · Advances in Wound Care · doi:10.1089/wound.2013.0503 · Cited by 132 · see citing works
“These include epidermal growth factor, fibroblast growth factor, ILs (IL-1 and IL-6), and cortisol among others.(44,46) Once closure is achieved, collagen is remodeled and realigned in the scar tissue, whereas excess of cells is removed by apoptosis, and barrier epidermal keratinocytes resume their role to properly re…”
BackgroundUVB activates hypothalamic-pituitary-adrenal axis in C57BL/6 mice
Skobowiat, C., & Slominski, A. T. (2015) · Journal of Investigative Dermatology · doi:10.1038/jid.2014.450 · Cited by 126 · see citing works
“, 2000c), which, after interaction with MC2R, induces steroidogenesis with the final production of highly adaptable COR or CORT (Cirillo and Prime, 2011; Ito et al., 2005; Skobowiat et al., 2011; Slominski et al., 2000a; Slominski et al., 2013a; Slominski et al., 2005a; Slominski et al., 2005b; Slominski et al., 2006a…”
BackgroundNeuro–immuno–endocrinology of the skin: how environment regulates body homeostasis
Slominski, R. M., Raman, C., Jetten, A. M., & Slominski, A. T. (2025) · Nature Reviews Endocrinology · doi:10.1038/s41574-025-01107-x · Cited by 133 · see citing works
“Production of glucocorticoids in epidermal and dermal skin cells has been well documented over the past two decades, as has their role in skin pathophysiology 77,102–104, 135– 139 .”
The role of estrogen deficiency in skin ageing and wound healing
Emmerson, E., & Hardman, M. J. (2012) · Biogerontology · doi:10.1007/s10522-011-9322-y · Cited by 118 · see citing works
“Additionally, local production of 11b-HSD by epidermal keratinocytes, dermal fibroblasts and hair follicles (Tiganescu et al. 2011) increases cortisol conversion and has been speculated to control the inflammatory response (Vukelic et al. 2011).”
BackgroundInfluentialKeratinocytes synthesize and activate cortisol
Cirillo, N., & Prime, S. S. (2011) · Journal of Cellular Biochemistry · doi:10.1002/jcb.23081 · Cited by 118 · see citing works
“The authors wish to acknowledge that two papers relevant to this article have recently appeared online (Hannen et al., 2011; Vukelic et al., 2011).”
BackgroundSkobowiat, C., Sayre, R. M., Dowdy, J. C., & Slominski, A. T. (2013) · British Journal of Dermatology · doi:10.1111/bjd.12096 · Cited by 115 · see citing works
Liu, Z., Hu, X., Liang, Y., Yu, J., Li, H., Shokhirev, M. N., & Zheng, Y. (2022) · Nature Immunology · doi:10.1038/s41590-022-01244-9 · Cited by 110 · see citing works
Implicating anaesthesia and the perioperative period in cancer recurrence and metastasis
Dubowitz, J. A., Sloan, E. K., & Riedel, B. (2017) · Clinical & Experimental Metastasis · doi:10.1007/s10585-017-9862-x · Cited by 103 · see citing works
The significance of CYP11A1 expression in skin physiology and pathology
Slominski, R. M., Raman, C., Elmets, C. A., Jetten, A. M., Slominski, A. T., & Tuckey, R. C. (2021) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2021.111238 · Cited by 97 · see citing works
Stress-linked cortisol concentrations in hair: what we know and what we need to know
Sharpley, C. F., McFarlane, J. R., & Slominski, A. (2012) · revneuro · doi:10.1515/rns.2011.058 · Cited by 92 · see citing works
Cytochromes P450 and Skin Cancer: Role of Local Endocrine Pathways
Slominski, A. T., Zmijewski, M. A., Semak, I. V., Zbytek, B., Pisarchik, A. V., Li, W., Zjawiony, J. K., & Tuckey, R. C. (2014) · Anti-Cancer Agents in Medicinal Chemistry · doi:10.2174/18715206113139990308 · Cited by 91 · see citing works
Skobowiat, C., Postlethwaite, A. E., & Slominski, A. T. (2016) · Photochemistry and Photobiology · doi:10.1111/php.12642 · Cited by 81 · see citing works
Jozic, I., Vukelic, S., Stojadinović, O., Liang, L., Ramirez, H. A., Pastar, I., & Tomic‐Canic, M. (2016) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2016.11.036 · Cited by 81 · see citing works
“We found that GCs are synthesized in epidermis and regulate inflammatory response during acute injury (Slominski et al., 2007; Slominski et al., 2005a; Slominski et al., 2005b; Slominski et al., 2004; Stojadinovic et al., 2007; Vukelic et al., 2011), whereas stress was found to impair wound healing (Stojadinovic et al.”
BackgroundInfluentialAdvanced Wound Diagnostics: Toward Transforming Wound Care into Precision Medicine
Weigelt, M. A., Lev‐Tov, H. A., Tomic‐Canic, M., Lee, W. D., Williams, R., Strasfeld, D. B., Kirsner, R. S., & Herman, I. M. (2021) · Advances in Wound Care · doi:10.1089/wound.2020.1319 · Cited by 82 · see citing works
Role of neuropeptides, neurotrophins, and neurohormones in skin wound healing
Chéret, J., Lebonvallet, N., Carré, J., Misery, L., & Gall‐Ianotto, C. L. (2013) · Wound Repair and Regeneration · doi:10.1111/wrr.12101 · Cited by 85 · see citing works
“IL-1β probably induces its own negative feedback regulation by inducing the expression CYP11B1, the essential enzyme for cortisol synthesis, and a subsequent increase in cortisol production by keratinocytes.(232) Chéret et al.”
BackgroundStojadinovic, O., Minkiewicz, J., Sawaya, A., Bourne, J. W., Torzilli, P., de Rivero Vaccari, J. P., Dietrich, W. D., Keane, R. W., & Tomic-Canic, M. (2013) · PLoS ONE · doi:10.1371/journal.pone.0069223 · Cited by 77 · see citing works
“8 mm sections were subjected to hematoxylin and eosin staining (H&E) and picrosirius red staining using previously described protocol [20,30,31].”
BackgroundMethodSelf-citationExtra-adrenal glucocorticoid synthesis: immune regulation and aspects on local organ homeostasis
Talabér, G., Jondal, M., & Okret, S. (2013) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2013.05.007 · Cited by 80 · see citing works
“An example of this is the improvement of skin wound healing following local administration of metyrapone, an inhibitor of GC synthesis (Vukelic et al., 2011).”
BackgroundInfluentialCutaneous glucocorticosteroidogenesis: securing local homeostasis and the skin integrity
Slominski, A. T., Manna, P. R., & Tuckey, R. C. (2014) · Experimental Dermatology · doi:10.1111/exd.12376 · Cited by 79 · see citing works
A neuroscience approach to managing athletes with low back pain
Puentedura, E. J., & Louw, A. (2011) · Physical Therapy in Sport · doi:10.1016/j.ptsp.2011.12.001 · Cited by 79 · see citing works
“Cortisol further alters cytokine levels, which in turn alters the immune system (the athlete may be more susceptible to infections) (Vukelic et al., 2011) and increase nerve sensitivity.”
BackgroundSkin steroidogenesis in health and disease
Nikolakis, G., Stratakis, C. A., Kanaki, T., Slominski, A., & Zouboulis, C. C. (2016) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-016-9390-z · Cited by 76 · see citing works
“Cortisol detection was also documented through RIA or ELISA in follicular [9, 34] or epidermal keratinocytes [18, 35, 36].”
Serradell, A., Torrecillas, S., Makol, A., Valdenegro, V., Fernández-Montero, Á., Acosta, F., Izquierdo, M. S., & Montero, D. (2020) · Fish & Shellfish Immunology · doi:10.1016/j.fsi.2020.03.016 · Cited by 77 · see citing works
Sawaya, A. P., Pastar, I., Stojadinović, O., Lazovic, S., Davis, S. C., Gil, J., Kirsner, R. S., & Tomic‐Canic, M. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.m117.811240 · Cited by 77 · see citing works
“Thewounds were quantified by planimetry as described previously (16, 53).”
BackgroundMethodInfluentialPastar, I., Sawaya, A. P., Marjanović, J., Burgess, J. L., Strbo, N., Rivas, K. E., Wikramanayake, T. C., Head, C. R., Stone, R. C., Jozic, I., et al. (2021) · Journal of Clinical Investigation · doi:10.1172/jci133727 · Cited by 76 · see citing works
“In addition, our laboratory has previously shown that IL-1β induces synthesis of epidermal cortisol, a potent wound healing inhibitor, resulting in impaired cell migration and wound closure (52-54).”
BackgroundRoles of the Glucocorticoid and Mineralocorticoid Receptors in Skin Pathophysiology
Sevilla, L. M., & Pérez, P. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19071906 · Cited by 72 · see citing works
Advances in the treatment of chronic wounds: a patent review
van Koppen, C. J., & Hartmann, R. W. (2015) · Expert Opinion on Therapeutic Patents · doi:10.1517/13543776.2015.1045879 · Cited by 71 · see citing works
“In accordance with these well-known actions of glucocorticoids, inhibitors of CYP11B1 have recently shown to strongly accelerate wound healing in ex vivo human skin wound models and in vivo porcine wound model ([6,9], own data: manuscript in preparation).”
BackgroundResultInfluentialSamotij, D., Nedoszytko, B., Bartosińska, J., Batycka-Baran, A., Czajkowski, R., Dobrucki, I. T., Dobrucki, L. W., Górecka-Sokołowska, M., Janaszak‐Jasiecka, A., Krasowska, D., et al. (2020) · Advances in Dermatology and Allergology · doi:10.5114/ada.2020.94832 · Cited by 68 · see citing works
“This termination of CRH/urocortin- or cytokineinduced proinflammatory activities can be mediated via indirect effects involving stimulation of POMC, the production and release of corticosteroids [160, 161, 164, 166], and POMC-peptides dependent downregulation of NF-kb activities in a context-dependent fashion [187, 21…”
BackgroundLocal glucocorticoid production in the mouse lung is induced by immune cell stimulation
Hostettler, N., Bianchi, P., Gennari‐Moser, C., Kassahn, D., Schoonjans, K., Corazza, N., & Brunner, T. (2011) · Allergy · doi:10.1111/j.1398-9995.2011.02749.x · Cited by 65 · see citing works
“Although steroid regulatory mechanisms are highly complex and encompass innumerable factors, IL-1b represents a promising candidate for future analysis, as it often synergizes with TNFa and has been shown to play a central role in extra-adrenal GC synthesis in the human skin (29).”
BackgroundContinuous free cortisol profiles-circadian rhythms in healthy men
Bhake, R. C., Kluckner, V, Stassen, H., Russell, G. M., Leendertz, J., Stevens, K., Linthorst, A. C. E., & Lightman, S. L. (2019) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2019-00449 · Cited by 64 · see citing works
Epigenetic regulation of cellular functions in wound healing
Pastar, I., Marjanović, J., Stone, R. C., Chen, V., Burgess, J. L., Mervis, J. S., & Tomic‐Canic, M. (2021) · Experimental Dermatology · doi:10.1111/exd.14325 · Cited by 60 · see citing works
Mevastatin promotes healing by targeting caveolin-1 to restore EGFR signaling
Sawaya, A. P., Jozic, I., Stone, R. C., Pastar, I., Egger, A. N., Stojadinović, O., Glinos, G. D., Kirsner, R. S., & Tomic‐Canic, M. (2019) · JCI Insight · doi:10.1172/jci.insight.129320 · Cited by 56 · see citing works
“Since skin is a site of extra-hepatic cholesterol synthesis and extra-adrenal site for cortisol synthesis, modulation of cholesterol and cortisol production can directly affect Cav1 and its control of wound closure (28-31).”
BackgroundControlling skin microbiome as a new bacteriotherapy for inflammatory skin diseases
Ito, Y., & Amagai, M. (2022) · Inflammation and Regeneration · doi:10.1186/s41232-022-00212-y · Cited by 58 · see citing works
“Additionally, major skin compartments such as the epidermis, dermis, and HFs have been shown to synthesize cortisol, an endogenous glucocorticoid that is administered as a potent anti-inflammatory drug for chronic inflammatory diseases [46, 47].”
BackgroundMadaro, A., Nilsson, J., Whatmore, P., Roh, H., Grove, S., Stien, L. H., & Olsen, R. E. (2022) · Fish Physiology and Biochemistry · doi:10.1007/s10695-022-01163-4 · Cited by 54 · see citing works
Human Ex Vivo Wound Healing Model
Stojadinović, O., & Tomic‐Canic, M. (2013) · Methods in molecular biology · doi:10.1007/978-1-62703-505-7_14 · Cited by 54 · see citing works
Endogenous Glucocorticoid Deficiency in Psoriasis Promotes Inflammation and Abnormal Differentiation
Sarkar, M. K., Kaplan, N., Tsoi, L. C., Xing, X., Liang, Y., Swindell, W. R., Hoover, P., Aravind, M. S., Baida, G. E., Clark, M. R., et al. (2017) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2017.02.972 · Cited by 54 · see citing works
“, 2011), HSD11B2 converts cortisol to the inactive cortisone (Cirillo and Prime, 2011; Miller and Auchus, 2011; Tiganescu et al., 2011; Vukelic et al., 2011) (Figure 3).”
BackgroundRendić, S., & Guengerich, F. P. (2018) · Drug Metabolism Reviews · doi:10.1080/03602532.2018.1483401 · Cited by 54 · see citing works
Taves, M. D., Otsuka, S., Taylor, M. A., Donahue, K. M., Meyer, T. J., Cam, M. C., & Ashwell, J. D. (2023) · Journal of Clinical Investigation · doi:10.1172/jci164599 · Cited by 52 · see citing works
“This is particularly the case at sites of immune cell activation such as the thymus (11–13), intestine (14, 15), and skin (16–18).”
Increased glucocorticoid activation during mouse skin wound healing
Tiganescu, A., Hupe, M., Uchida, Y., Mauro, T. M., Elias, P. M., & Holleran, W. M. (2014) · Journal of Endocrinology · doi:10.1530/joe-13-0420 · Cited by 48 · see citing works
“Recently, a study using human and porcine models has indicated that steroidogenesis contributes directly to increased GC levels generated during wound healing (Vukelic et al. 2011).”
BackgroundInfluentialDysfunctional Skin-Derived Glucocorticoid Synthesis Is a Pathogenic Mechanism of Psoriasis
Hannen, R. F., Udeh‐Momoh, C. T., Upton, J. H., Wright, M., Michael, A. E., Gulati, A., Rajpopat, S., Clayton, N., Halsall, D. J., Burrin, J. M., et al. (2017) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2017.02.984 · Cited by 49 · see citing works
“…an integral component of many topical psoriasis therapies, and healthy keratinocytes can synthesise GC de novo (Cirillo and Prime 2011; Hannen et al. 2011; Vukelic et al. 2011; et al. 2016), we hypothesise that loss of effective skin-GC synthesis forms a novel pathogenic mechanism of psoriasis.”
BackgroundTrace amines produced by skin bacteria accelerate wound healing in mice
Luqman, A., Muttaqin, Z., Yulaipi, S., Ebner, P., Matsuo, M., Zabel, S., Tribelli, P. M., Nieselt, K., Hidayati, D., & Götz, F. (2020) · Communications Biology · doi:10.1038/s42003-020-1000-7 · Cited by 49 · see citing works
Day, Y., Liou, J.-T., Lee, C.-M., Lin, Y., Mao, C.-C., Chou, A., Liao, C.-C., & Lee, H.-C. (2014) · Pain · doi:10.1016/j.pain.2014.04.004 · Cited by 47 · see citing works
“However, the protective role of IL-1b signaling was also observed in a rat traumatic brain injury model [19], in a rat intestinal reperfusion injury model [34], and in an epidermis disorder [38].”
BackgroundStress, the neuroendocrine system and mast cells: current understanding of their role in psoriasis
Harvima, I. T., & Nilsson, G. P. (2012) · Expert Review of Clinical Immunology · doi:10.1586/eci.12.1 · Cited by 47 · see citing works
Glucocorticoid receptors, epidermal homeostasis and hair follicle differentiation
Pérez, P. (2011) · Dermato-Endocrinology · doi:10.4161/derm.15332 · Cited by 45 · see citing works
Hair cortisol in the evaluation of Cushing syndrome
Hodes, A. D., Lodish, M. B., Tirosh, A., Meyer, J. S., Belyavskaya, E., Lyssikatos, C., Rosenberg, K. L., Demidowich, A. P., Swan, J., Jonas, N., et al. (2017) · Endocrine · doi:10.1007/s12020-017-1231-7 · Cited by 46 · see citing works
“As may be seen in adrenal tissue in ACTHdependent CS, in vitro studies of cultured skin sections have shown doubling to tripling of cortisol production after exposure to ACTH [48].”
Nguyen, V. T., Farman, N., Maubec, E., Nassar, D., Desposito, D., Waeckel, L., Aractingi, S., & Jaisser, F. (2016) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2016.05.101 · Cited by 44 · see citing works
“For example, HSD2 mRNA or protein levels were reported to be low under control conditions, but enhanced following UVA exposure or wounding (Vukelic et al., 2011; Skobowiat et al., 2013; Tiganescu et al, 2014).”
BackgroundPharmacological and Genetic Inhibition of Caveolin-1 Promotes Epithelialization and Wound Closure
Jozic, I., Sawaya, A. P., Pastar, I., Head, C. R., Wong, L. L., Glinos, G. D., Wikramanayake, T. C., Brem, H., Kirsner, R. S., & Tomic‐Canic, M. (2019) · Molecular Therapy · doi:10.1016/j.ymthe.2019.07.016 · Cited by 43 · see citing works
Genetic variation of the cutaneous HPA axis: an analysis of UVB-induced differential responses
Skobowiat, C., Nejati, R., Lu, L., Williams, R. W., & Slominski, A. T. (2013) · Gene · doi:10.1016/j.gene.2013.08.035 · Cited by 42 · see citing works
“However, both strains reacted similarly in terms of general induction ACTH and CORT production with D2 showing nevertheless higher level of sensitivity at lower doses and shorter time of UVB exposure (Fig.”
BackgroundInfluentialPlant-Derived Medicines with Potential Use in Wound Treatment
Maver, T., Kurečič, M., Smrke, D. M., Kleinschek, K. S., & Maver, U. (2019) · IntechOpen eBooks · doi:10.5772/intechopen.72813 · Cited by 42 · see citing works
“Epithelialisation is initiated by keratinocytes proliferating and migrating across the wound site [8].”
Cirillo, N., Morgan, D. J., Pedicillo, M. C., Celentano, A., Muzio, L. L., McCullough, M. J., & Prime, S. S. (2017) · British Journal of Cancer · doi:10.1038/bjc.2017.243 · Cited by 40 · see citing works
“In the skin, steroidogenesis is involved in the modulation of a variety of physiological functions (Slominski et al, 2000; Vukelic et al, 2011; Kennedy et al, 2015).”
BackgroundInfluentialBoix, J., Sevilla, L. M., Sáez, Z., Carceller, E., & Pérez, P. (2016) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2016.07.018 · Cited by 39 · see citing works
“It is also widely recognized that epidermal keratinocytes are able to synthesize GCs in response to wounding; consistently, local blockade of GC production using inhibitors of 11b-hydroxysteroid dehydrogenase type 1 accelerated wound healing (Slominski et al., 2014; Tiganescu et al., 2013; Vukelic et al., 2011; Youm e…”
BackgroundSkin under the (Spot)-Light: Cross-Talk with the Central Hypothalamic-Pituitary-Adrenal (HPA) Axis
Jozic, I., Stojadinovic, O., Kirsner, R. S. F., & Tomic-Canic, M. (2015) · Journal of Investigative Dermatology · doi:10.1038/jid.2015.56 · Cited by 38 · see citing works
Stress-Induced Hormones Cortisol and Epinephrine Impair Wound Epithelization
Stojadinović, O., Gordon, K. A., Lebrun, E. A., & Tomic‐Canic, M. (2012) · Advances in Wound Care · doi:10.1089/wound.2011.0320 · Cited by 38 · see citing works
“Cortisol production by keratinocytes can be induced by IL-1b during wound healing and, on the contrary, inhibition of cortisol synthesis can induce IL-1b production.(3) Importantly, CYP11B1 expression and cortisol production is regulated during acute wound healing.”
BackgroundInfluentialTranscriptional regulation of wound inflammation
Haertel, E., Werner, S., & Schäfer, M. (2014) · Seminars in Immunology · doi:10.1016/j.smim.2014.01.005 · Cited by 37 · see citing works
Preclinical models for wound-healing studies
Pastar, I., Liang, L., Sawaya, A. P., Wikramanayake, T. C., Glinos, G. D., Drakulich, S., Chen, V., Stojadinović, O., Davis, S. C., & Tomic‐Canic, M. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-810545-0.00010-3 · Cited by 39 · see citing works
Glucocorticoids Influencing Wnt/β-Catenin Pathway; Multiple Sites, Heterogeneous Effects
Mészáros, K. V., & Patócs, A. (2020) · Molecules · doi:10.3390/molecules25071489 · Cited by 37 · see citing works
Islam, M. M., Ramesh, V. H., Bhavani, P. D., Prakash Goudanavar, S. O. P., Naveen, N. R., Ramesh, B., Fattepur, S., Shiroorkar, P. N., Habeebuddin, M., Meravanige, G., et al. (2022) · Drug Delivery · doi:10.1080/10717544.2022.2144963 · Cited by 38 · see citing works
“Ultimately, keratinocyte proliferation starts reepithelialization (Vukelic et al., 2011).”
BackgroundTerao, M., Tani, M., Itoi, S., Yoshimura, T., Hamasaki, T., Murota, H., & Katayama, I. (2014) · PLoS ONE · doi:10.1371/journal.pone.0093051 · Cited by 36 · see citing works
“Recently, local cortisol/corticosterone production in the skin via a de novo pathway and via the cortisol activating enzyme, 11bhydroxysteroid dehydrogenase (11b-HSD) has been reported [18,19,20,21,22,23,24,25,26,27].”
BackgroundAoki, R., AOKI-YOSHIDA, A., Suzuki, C., & Takayama, Y. (2014) · PLoS ONE · doi:10.1371/journal.pone.0096804 · Cited by 36 · see citing works
“[34] Glucocorticoid treatment of keratinocytes inhibits production of inflammatory mediators.”
BackgroundTreatment Strategies Against Diabetic Foot Ulcer: Success so Far and the Road Ahead
Awasthi, A., Singh, S. K., Kumar, B., Gulati, M., Kumar, R., Wadhwa, S., Khursheed, R., Corrie, L., Ramanunny, A. K., Kumar, R., et al. (2020) · Current Diabetes Reviews · doi:10.2174/1573399816999201102125537 · Cited by 38 · see citing works
Keratinocyte-Targeted Overexpression of the Glucocorticoid Receptor Delays Cutaneous Wound Healing
Sanchis, A., Alba, L., Latorre, V., Sevilla, L. M., & Pérez, P. (2012) · PLoS ONE · doi:10.1371/journal.pone.0029701 · Cited by 35 · see citing works
“This highlights the relevance of locally produced GCs and likely represents a feed-back mechanism to modulate GC-mediated signaling and mitigate the initial pro-inflammatory responses [27].”
BackgroundDolah, F. M. V., Neely, M. G., McGeorge, L. E., Balmer, B. C., Ylitalo, G. M., Zolman, E. S., Speakman, T. R., Sinclair, C., Kellar, N. M., Rosel, P. E., et al. (2015) · PLoS ONE · doi:10.1371/journal.pone.0130934 · Cited by 35 · see citing works
“Human epidermal keratinocytes synthesize cortisol and regulate its synthesis and activity in response to wounding [51].”
Background11β-Hydroxysteroid dehydrogenase 1 contributes to the pro-inflammatory response of keratinocytes
Itoi, S., Terao, M., Murota, H., & Katayama, I. (2013) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2013.09.065 · Cited by 34 · see citing works
Host–Microbiome Crosstalk in Chronic Wound Healing
Mihai, M. M., Bălăceanu-Gurău, B., Ion, A., Holban, A. M., Gurău, C.-D., Popescu, M. N., Beiu, C., Popa, L. G., Popa, M. I., Dragomirescu, C. C., et al. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25094629 · Cited by 34 · see citing works
“The main issue resulting from these series of events is that migratory rates of keratinocytes are remarkably lowered by cortisol, farnesyl pyrophosphate, adrenaline, and other β 2AR agonists, pointing at their role in the inhibition of proper re-epithelization [74,75,77].”
BackgroundTakei, K., Denda, S., Kumamoto, J., & Denda, M. (2013) · Experimental Dermatology · doi:10.1111/exd.12224 · Cited by 33 · see citing works
Stressing the Steroids in Skin: Paradox or Fine-Tuning?
Jozic, I., Stojadinović, O., Kirsner, R. S., & Tomic‐Canic, M. (2014) · Journal of Investigative Dermatology · doi:10.1038/jid.2014.363 · Cited by 32 · see citing works
“Clinical impact of GC-based therapies GCs are widely used as anti-inflammatory drugs, and adverse effects of prolonged local and systemic GC treatment in the skin and in many other tissues are known to occur (Vukelic et al., 2011).”
BackgroundInfluentialOptical coherence tomography for assessment of epithelialization in a human ex vivo wound model
Glinos, G. D., Verne, S. H., Aldahan, A. S., Liang, L., Nouri, K., Elliot, S. J., Glassberg, M. K., DeBuc, D. C., Koru‐Sengul, T., Tomic‐Canic, M., et al. (2017) · Wound Repair and Regeneration · doi:10.1111/wrr.12600 · Cited by 32 · see citing works
Glucocorticoid metabolism in the developing lung: adrenal-like synthesis pathway
Provost, P. R., Boucher, E., & Tremblay, Y. (2013) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2013.03.004 · Cited by 31 · see citing works
“Few mature tissues express either several or all genes of the cascade, but in several cases, production of corticosterone or aldosterone is stimulated by specific conditions such as local tissue damage [83], immune activation [84, 85], inflammation [86, 87], or pathological conditions [88].”
BackgroundCharacterization of a Novel Oral Glucocorticoid System and Its Possible Role in Disease
Cirillo, N., Hassona, Y. M., Pignatelli, M. N., Gasparoto, T. H., Morgan, D. J. W., & Prime, S. S. (2011) · Journal of Dental Research · doi:10.1177/0022034511427909 · Cited by 31 · see citing works
“…while previous work has focused on the conversion of steroidal intermediates to glucocorticoids via the cytochrome P450 chain, the demonstration that ACTH alone can induce de novo synthesis of hydrocortisone in skin keratinocytes is recent (Cirillo and Prime, 2011; Vukelic et al., 2011).”
BackgroundTerao, M., Itoi, S., Murota, H., & Katayama, I. (2012) · Experimental Dermatology · doi:10.1111/exd.12075 · Cited by 29 · see citing works
Mateus, A. P., Anjos, L., Cardoso, J. C. R., & Power, D. M. (2017) · Molecular Immunology · doi:10.1016/j.molimm.2017.04.008 · Cited by 30 · see citing works
Detection of endogenous cortisol in equine tears and blood at rest and after simulated stress
Monk, C. S., Hart, K. A., Berghaus, R. D., Norton, N. A., Moore, P. A., & Myrna, K. E. (2013) · Veterinary Ophthalmology · doi:10.1111/vop.12128 · Cited by 29 · see citing works
Extra-adrenal glucocorticoid synthesis at epithelial barriers
Phan, T. S., Merk, V. M., & Brunner, T. (2019) · Genes and Immunity · doi:10.1038/s41435-019-0058-z · Cited by 28 · see citing works
“layer of the epidermis, Cyp11b1 is predominantly expressed by basal layer keratinocytes [52, 98].”
BackgroundLocal Glucocorticoid Activation by 11β-Hydroxysteroid Dehydrogenase 1 in Keratinocytes
Terao, M., Itoi, S., Matsumura, S., Yang, L., Murota, H., & Katayama, I. (2016) · American Journal Of Pathology · doi:10.1016/j.ajpath.2016.01.014 · Cited by 28 · see citing works
How does epidermal pathology interact with mental state?
Denda, M., Takei, K., & Denda, S. (2012) · Medical Hypotheses · doi:10.1016/j.mehy.2012.11.027 · Cited by 27 · see citing works
Taves, M. D., Plumb, A. W., Korol, A. M., van der Gugten, J. G., Holmes, D. T., Abraham, N. B., & Soma, K. K. (2016) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2016.05.003 · Cited by 27 · see citing works
“All tissues were dispersed with a pipette, and incubated for 24 h in 5% CO2 at 37 "C in 4 ml medium containing vehicle (0.2% ethanol), 0.9 mM metyrapone (Vacchio and Ashwell, 1997; Cima et al., 2004; Tocris), or 1 lM DOC or DHC steroid substrate (Vukelic et al., 2011; Steraloids) (Fig.”
MethodInfluentialDifferentiation of Keratinocytes Modulates Skin HPA Analog
Wierzbicka, J., Zmijewski, M. A., Antoniewicz, J., Sobjanek, M., & Slominski, A. T. (2016) · Journal of Cellular Physiology · doi:10.1002/jcp.25400 · Cited by 27 · see citing works
“…enzymes involved in cortisol synthesis CYP11A1 (Slominski et al., 1996b, 2004c) and 11bHSD1 (Tiganescu et al., 2011) were shown to be wildly expressed in epidermis, however CYP11B1 was detected only in basal keratinocytes and first layer of suprabasal cells (Mapligian layer) (Vukelic et al., 2011).”
BackgroundPastar, I., Stojadinović, O., Sawaya, A. P., Stone, R. C., Lindley, L. E., Ojeh, N. O., Vukelic, S., Samuels, H. H., & Tomic‐Canic, M. (2016) · Journal of Cellular Physiology · doi:10.1002/jcp.25357 · Cited by 26 · see citing works
“It is possible that FPP, upon binding to GR ligand binding domain, causes a slightly different conformational change than GCs and acts as a partial agonist or mixed agonist-antagonist.”
BackgroundInfluentialA test of reactive scope: Reducing reactive scope causes delayed wound healing
DuRant, S. E., Arciniega, M. L., Bauer, C. M., & Romero, L. M. (2016) · General and Comparative Endocrinology · doi:10.1016/j.ygcen.2016.07.013 · Cited by 26 · see citing works
Wang, B., Zhao, J., Lu, W., Ma, Y., Wang, X., An, X., & Fan, Z. (2022) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2022.09.126 · Cited by 26 · see citing works
Lattin, C. R., Waldron-Francis, K., & Romero, L. M. (2013) · Proceedings of the Royal Society B Biological Sciences · doi:10.1098/rspb.2012.3033 · Cited by 26 · see citing works
“Not only can systemic CORT affect skin immune processes, but there is also evidence of local glucocorticoid synthesis in mammalian skin [55], which can be induced by wounding [56].”
Background
- Authors
- Vukelic, S., Stojadinovic, O., Pastar, I., Rabach, M., Krzyzanowska, A., Lebrun, E., Davis, S. C., Resnik, S., Brem, H., & Tomic-Canic, M.
- Affiliations
- Lenox Hill Hospital (US)
- University of Miami (US)
- SUNY Downstate Health Sciences University (US)
- Hospital for Special Surgery (US)
- NYU Langone Health (US)
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2011-03
- Volume
- 286
- Issue
- 12
- Pages
- 10265-10275
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3060481
- OpenAlex
- W2080660266
- Cited by
- 193
- References
- 67
- Citations by year
- 2026: 6 · 2025: 12 · 2024: 7 · 2023: 6 · 2022: 12 · 2021: 11 · 2020: 18 · 2019: 9 · 2018: 11 · 2017: 18 · 2016: 17 · 2015: 8 · 2014: 15 · 2013: 19 · 2012: 13
- FWCI
- 18.81
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Nursing Research (R01NR008029, NR008029)
- National Institute of Diabetes and Digestive and Kidney Diseases (K24DK090135)
- Topics
- Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Health Sciences › Medicine › Pharmacology › Inflammatory mediators and NSAID effects
- Keywords
- cortisol production, epidermis, keratinocytes, wound healing, IL-1β, tissue damage, CYP11B1, 11β-hydroxysteroid dehydrogenase type 2, glucocorticoid receptor, ACTH, metyrapone, negative feedback regulation, inflammatory cytokines
- MeSH terms
- Adrenocorticotropic Hormone, Animals, Enzyme Inhibitors, Epidermis, Hormones, Humans, Hydrocortisone, Inflammation, Metyrapone, Steroid 11-beta-Hydroxylase, Swine, Wound Healing, Keratinocytes, Interleukin-1beta
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