IL-17A induces heterogeneous macrophages, and it does not alter the effects of lipopolysaccharides on macrophage activation in the skin of mice.

Macrophages are central to inflammatory response and become polarized towards the M1 or M2 states upon activation by immunostimulants. In this study, we investigated the effects of lipopolysaccharides (LPS) and interleukin (IL)-17A on the activation of macrophages in in vivo mouse skin. We examined whether macrophages are activated in the skin of imiquimod (IMQ)-treated mice, a model for IL-17A-induced psoriasis-like skin inflammation, and flaky-tail (Flg ft ) mice, a model for IL-17A-induced chronic atopic dermatitis-like skin inflammation. LPS and IL-17A independently increased the expression levels of iNOS, CX3CR1, CD206, phospho-STAT1 and phospho-STAT3 proteins in the skin of B6 mice, and the effects of LPS was not altered by IL-17A. The expression levels of these proteins were increased in the skin of IMQ-treated and Flg ft mice. IL-17A neutralization increased the expressions of iNOS and phospho-STAT1 in the IMQ-treated skin, but it decreased the expressions of CD206 and phospho-STAT3 proteins in the skin of Flg ft mice, suggesting that macrophages to change from the M2 to the M1 state in the skin of these mice. These results suggest that IL-17A is involved in the activation of macrophages that are in the process of adopting the heterogeneous profiles of both the M1 and M2 states.

Deranged epidermal differentiation in kl/kl mouse and the effects of ßKlotho siRNA on the differentiation of HaCaT cells.

Mice deficient in the klotho gene (kl/kl mice) display the phenotypes of human ageing. We found that the expression of epidermal differentiation-associated factors (keratin 1, keratin 10, filaggrin and loricrin) was lower in the skin of kl/kl mice than that of wild-type mice. In vitro experiments showed that the expression of ßKlotho, a family of klotho gene-encoded protein, was induced concomitantly with the differentiation of an immortalized human epidermal keratinocyte cell line (HaCaT cells) when they were cultured in an air-liquid interface. ßKlotho knockdown by small interfering ribonucleic acid suppressed the expression of the above differentiation-associated factors in HaCaT cells. ßKlotho small interfering ribonucleic acid increased the expression of keratin 14, which is expressed in mitotically active basal layer cells, and activated p44/p42 mitogen-activated protein kinase in the HaCaT cells grown in the air-liquid interface. These findings suggest that the epidermal differentiation is deranged in kl/kl mice, and ßKlotho is required for the differentiation of human epidermal keratinocytes.

Dexamethasone induces caveolin-1 in vascular endothelial cells: implications for attenuated responses to VEGF.

Steroids exert direct actions on cardiovascular cells, although underlying molecular mechanisms remain incompletely understood. We examined if steroids modulate abundance of caveolin-1, a regulatory protein of cell-surface receptor pathways that regulates the magnitudes of endothelial response to vascular endothelial growth factor (VEGF). Dexamethasone, a synthetic glucocorticoid, induces caveolin-1 at both levels of protein and mRNA in a time- and dose-dependent manner in pharmacologically relevant concentrations in cultured bovine aortic endothelial cells. Aldosterone, a mineralocorticoid, but not the sex steroids 17ß-estradiol, testosterone, or progesterone, elicits similar caveolin-1 induction. Caveolin-1 induction by dexamethasone and that by aldosterone were abrogated by RU-486, an inhibitor of glucocorticoid receptor, and by spironolactone, a mineralocorticoid receptor inhibitor, respectively. Dexamethasone attenuates VEGF-induced responses at the levels of protein kinases Akt and ERK1/2, small-G protein Rac1, nitric oxide production, and migration. When induction of caveolin-1 by dexamethasone is attenuated either by genetically by transient transfection with small interfering RNA or pharmacologically by RU-486, kinase responses to VEGF are rescued. Dexamethasone also increases expression of caveolin-1 protein in cultured human umbilical vein endothelial cells, associated with attenuated tube formation responses of these cells when cocultured with normal fibroblasts. Immunohistochemical analyses revealed that intraperitoneal injection of dexamethasone induces endothelial caveolin-1 protein in thoracic aorta and in lung artery in healthy male rats. Thus steroids functionally attenuate endothelial responses to VEGF via caveolin-1 induction at the levels of signal transduction, migration, and tube formation, identifying a novel point of cross talk between nuclear and cell-surface receptor signaling pathways.

A survey of the factors associated with concerns about oral antihistamine use in Japanese pruritic skin disease patients.

BACKGROUND: To improve health outcomes during the treatment for pruritic skin diseases, it is important to understand which factors most influence patients' concerns about oral antihistamine drugs. OBJECTIVES: To survey the nature of patients' concerns about oral antihistamine drugs and to examine the factors associated with them. METHODS: Patients with pruritic skin diseases expressed their concerns regarding the use of oral antihistamine drugs. The independent effects of the patients' background characteristics on their concerns were examined by multiple logistic regression analysis. RESULTS: A total of 291 outpatients were completed the study. Overall, 32% of patients were worried about using oral antihistamine drugs. The most common concern was about their adverse drug events (except drowsiness) and the effects of long-term use. Overall, being concerned about antihistamine use was found to be significantly and independently associated with a younger age, severe itching, being a homemaker, and having previous personal experience of embarrassment due to drowsiness caused by taking over-the-counter drugs. CONCLUSIONS: Several factors are associated with altered self-reported concerns about antihistamines. Our results suggest the importance of understanding the nature of patients' fears about oral antihistamine use so that sound advice can be offered to them in a timely manner.

Reduced expression of epidermal growth factor receptor, E-cadherin, and occludin in the skin of flaky tail mice is due to filaggrin and loricrin deficiencies.

Disruption of skin barrier function leads to increases in the percutaneous transfer of allergens and the incidence of atopic dermatitis. Flaky tail (Flg(ft)) mice have been used as a model of atopic dermatitis with skin barrier dysfunction. Although Flg(ft) mice are known to have filaggrin mutation, the mechanism responsible for the skin barrier dysfunction that they display needs to be determined, especially for the roles of epidermal adhesion and junction proteins. Herein, we report the decreased expression of epidermal growth factor receptor (EGFR), E-cadherin, occludin, and SIRT1 in the skin of Flg(ft) mice, compared with those in C57BL/6J mice. Administration of N-acetyl-L-cysteine, an antioxidant, in the drinking water improved these protein expressions in the skin of Flg(ft) mice. Notably, we discovered that loricrin expression was suppressed in Flg(ft) mice. In vitro experiments showed that filaggrin small interfering RNA, loricrin small interfering RNA, or SIRT1 inhibitor sirtinol suppressed the expression levels of EGFR, E-cadherin, and occludin in a human immortalized keratinocyte cell line (HaCaT cells). Our findings suggest that the observed reductions in EGFR, E-cadherin, and occludin expression were due to filaggrin deficiency accompanied with subsequent loricrin deficiency and disruption of the SIRT1 pathway in the skin of Flg(ft) mice.

Effect of sequential application of topical adapalene and clindamycin phosphate in the treatment of Japanese patients with acne vulgaris.

The efficacy of combined therapy with a retinoid and antibiotic for Japanese patients with acne vulgaris remains to be established. Further, maintenance strategies limiting the use of topical retinoids must be identified. The objectives of this study are to determine the efficacy of sequential application of topical adapalene and clindamycin phosphate and to assess the impact of this regimen on patients' quality of life. Sixty-six patients were recruited. The regimen comprised two phases. For the 4-week initial treatment, 1% clindamycin phosphate gel was applied twice daily and 0.1% adapalene gel, once. In the 4-week maintenance phase, patients were randomly assigned to the OD group (adapalene applied once daily) or the TW group (adapalene applied once daily on 2 days per week). The acne severity score, lesion counts, microcomedone count, and sebum amount were measured. Quality of life (QOL) was assessed using Skindex-16. All parameters improved significantly by week 4 of initial treatment. No statistically significant differences were found in the improvement of clinical findings between the groups. All QOL scores improved significantly and did not significantly differ between the groups. Our regimen may enable clinical control of acne in Japanese patients and improve their QOL. For limiting retinoid use, weekly application of adapalene during maintenance is suitable.

Combination effects of cosmetic moisturisers in the topical treatment of acne vulgaris.

Cosmetic moisturisers were applied to one side of the face of 18 male Japanese patients with acne vulgaris who were treated with a topical administration of adapalene and clindamycin phosphate gels. We assessed the alleviating effect of the moisturisers on the side effects of the treatment. The severity of acne and the number of inflammatory and non-inflammatory lesions were measured at 0, 2, and 4 weeks. The water content in the stratum corneum and transepidermal water loss were measured by comparing the moisturiser-treated and untreated sides of the face. The sensation of skin dryness and irritation on both sides of the face were assessed by the subjects. We observed that the use of moisturisers did not impact the efficacy of the standard topical treatment and they significantly improved the water content in the stratum corneum and the sensation of dryness. These results suggested that the use of moisturisers in combination with the standard topical treatment may improve adherence to therapy by alleviating the sensation of dryness.