Chronic stress weakens the skin barrier function owing to increased cortisol sensitivity through the imbalance in the expression of cortisol-metabolizing enzymes
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Presented by: Hiroyasu Iwahashi
Introduction: Cortisol is a hormone released into the blood during physical and psychological stress. Cortisol has negative effects on the body when it is maintained at high levels for prolonged durations owing to psychological stress. Cortisol has been reported to cause skin problems such as wrinkles, dry skin, and rough skin. For example, in in vitro studies, cortisol reduces the expression of tight junction genes related to the barrier function in epidermal keratinocytes. Although the temporary state of high cortisol concentration is caused by physical stress or chronotype, skin problems occur only in chronic conditions of high cortisol concentration. Thus, clarifying the effect of high cortisol conditions on epidermal keratinocytes is important for examining the influence of chronic stress conditions on the skin. Cortisol exerts various physiological actions by binding to glucocorticoid receptors in cells. Cortisol-metabolizing enzymes, 11β-hydroxysteroid dehydrogenases (11βHSDs), are present in cells and regulate intracellular cortisol concentration. 11βHSD-1 converts inactive cortisone to active cortisol, and 11βHSD-2 converts cortisol to cortisone. Therefore, cortisol binding to glucocorticoid receptors is regulated by the cortisol metabolic balance, which depends on the expression level of 11βHSDs. Moreover, cortisol has been reported to increase the expression of 11βHSD-1, which also affects metabolic balance. However, the relationship between stress and the ability to metabolize cortisol in the skin has not been completely elucidated. In this study, we investigated the relationship between cortisol exposure and the metabolic capacity of 11βHSDs in keratinocytes and the mechanism of the negative effects on the skin owing to chronic stress. Furthermore, we screened for natural extracts that could improve skin problems caused by chronic stress.
Method: Normal human epidermal keratinocytes (NHEKs) were treated with 20 µM cortisol once every 3 days or daily to induce temporary or chronic stress. To compare the difference in cortisol metabolism between these cells, 11βHSD-1 and 11βHSD-2 mRNA expression levels were measured by real-time RT-PCR. Cells seeded in Transwell were differentiated under calcium in the presence or absence of 20 µM cortisol, and the increase in transepithelial electrical resistance (TEER) was evaluated as an index of barrier function. The extracellular cortisol concentration when cortisone was added to NHEKs was measured by ELISA to evaluate the ability to regulate cortisol concentration.
Results and Discussion: To clarify whether metabolic capacity of 11βHSDs was affected differently by temporary or chronic stress, we evaluated the change in expression levels of 11βHSD-1 and 11βHSD-2 depending on the cortisol treatment method to NHEKs. First, in temporarily stressed cells, 11βHSD-1 mRNA expression did not increase as compared with that in the control after 72 h, whereas 11βHSD-2 mRNA expression was clearly increased. In contrast, in chronically stressed cells, 11βHSD-1 mRNA expression increased under the same conditions, whereas that of 11βHSD-2 did not. These results indicate that temporary cortisol treatment reduces the effect of cortisol by inducing 11βHSD-2, whereas continuous cortisol treatment maintains a high concentration of intracellular cortisol by inducing 11βHSD-1 but not 11βHSD-2. Although the addition of cortisol to NHEKs during the induction of differentiation showed a clear decrease in TEER compared to that in the control, a further decrease in TEER was observed in chronically stressed cells, but not in temporarily stressed cells. These results suggested that the repetitive supply of cortisol to NHEKs altered 11βHSDs expression levels, which may lead to skin problems under chronic stress. Regulating the metabolic capacity of 11βHSDs is likely to reduce the negative effects of chronic stress. Therefore, we screened natural extracts using cortisol metabolism as an index and found several natural extracts that reduced the extracellular cortisol released from NHEKs.
Conclusion: The maintenance of high cortisol levels owing to chronic psychological stress may intensify the sensitivity to cortisol by changing the expression levels of 11βHSD-1 and 11βHSD-2 and boost the influence of cortisol on the epidermis and excessively attenuate the barrier function. Hence, natural extracts that regulate the metabolic activity of 11βHSDs can be expected to prevent or improve the skin problems caused by chronic stress.
Method: Normal human epidermal keratinocytes (NHEKs) were treated with 20 µM cortisol once every 3 days or daily to induce temporary or chronic stress. To compare the difference in cortisol metabolism between these cells, 11βHSD-1 and 11βHSD-2 mRNA expression levels were measured by real-time RT-PCR. Cells seeded in Transwell were differentiated under calcium in the presence or absence of 20 µM cortisol, and the increase in transepithelial electrical resistance (TEER) was evaluated as an index of barrier function. The extracellular cortisol concentration when cortisone was added to NHEKs was measured by ELISA to evaluate the ability to regulate cortisol concentration.
Results and Discussion: To clarify whether metabolic capacity of 11βHSDs was affected differently by temporary or chronic stress, we evaluated the change in expression levels of 11βHSD-1 and 11βHSD-2 depending on the cortisol treatment method to NHEKs. First, in temporarily stressed cells, 11βHSD-1 mRNA expression did not increase as compared with that in the control after 72 h, whereas 11βHSD-2 mRNA expression was clearly increased. In contrast, in chronically stressed cells, 11βHSD-1 mRNA expression increased under the same conditions, whereas that of 11βHSD-2 did not. These results indicate that temporary cortisol treatment reduces the effect of cortisol by inducing 11βHSD-2, whereas continuous cortisol treatment maintains a high concentration of intracellular cortisol by inducing 11βHSD-1 but not 11βHSD-2. Although the addition of cortisol to NHEKs during the induction of differentiation showed a clear decrease in TEER compared to that in the control, a further decrease in TEER was observed in chronically stressed cells, but not in temporarily stressed cells. These results suggested that the repetitive supply of cortisol to NHEKs altered 11βHSDs expression levels, which may lead to skin problems under chronic stress. Regulating the metabolic capacity of 11βHSDs is likely to reduce the negative effects of chronic stress. Therefore, we screened natural extracts using cortisol metabolism as an index and found several natural extracts that reduced the extracellular cortisol released from NHEKs.
Conclusion: The maintenance of high cortisol levels owing to chronic psychological stress may intensify the sensitivity to cortisol by changing the expression levels of 11βHSD-1 and 11βHSD-2 and boost the influence of cortisol on the epidermis and excessively attenuate the barrier function. Hence, natural extracts that regulate the metabolic activity of 11βHSDs can be expected to prevent or improve the skin problems caused by chronic stress.