Yasuyuki Sumikawa

ΔNp63 Controls a TLR3-Mediated Mechanism That Abundantly Provides Thymic Stromal Lymphopoietin in Atopic Dermatitis

In the skin lesions of atopic dermatitis (AD), keratinocytes release large quantities of thymic stromal lymphopoietin (TSLP), causing unfavorable inflammation along with skin damage. Nevertheless, how TSLP influences keratinocytes themselves is still unknown. In this study, we showed that ΔNp63, a p53-homologue, predominantly expressed in keratinocytes regulated the receptor complex of TSLP, which determines susceptibility to self-derived TSLP. Expression of TSLP receptors in skin tissues and keratinocytes was assessed by immunohistochemistry and quantitative RT-PCR, and in vitro studies were also performed to examine the functional relevance of ΔNp63 in the expression of TSLP receptors and the constituting autocrine and/or paracrine pathway of TSLP under the condition of stimuli to innate receptors sensing cell damage. The results showed that normal keratinocytes in the upper epidermis preferentially expressed TSLP receptors and conversely lacked ΔNp63, which has an inhibitory effect on the expression of TSLP receptors. Interestingly, the epidermis of AD lesions was found to abundantly contain keratinocytes with low or undetectable levels of ΔNp63 (ΔNp63lo/-). Moreover, in the absence of ΔNp63, keratinocytes readily presented TSLP and other cytokines by stimuli through Toll-like receptor 3 (TLR3). Together with the evidence that extrinsic TSLP itself augments TSLP production by keratinocytes without ΔNp63, the results indicate that ΔNp63lo/- keratinocytes generate TSLP through a putative autocrine and/or paracrine pathway upon TLR3 stimulation within AD lesions, since moieties of damaged cells and pathogens stimulate TLR3.

Keratinocytes in atopic dermatitis express abundant ΔNp73 regulating thymic stromal lymphopoietin production via NF-κB

BACKGROUND Atopic dermatitis (AD) is a chronic inflammatory skin disease that often cannot be completely controlled by modern medicine. Since multiple factors are intricately involved in the pathogenesis of AD, wide-ranging research is required for further advancement of AD treatment. Epidermal keratinocytes are the forefront to the external environment and play a pivotal role in the initiation of immune reaction against exogenous invasion. OBJECTIVE Thymic stromal lymphopoietin (TSLP) is a keratinocyte-derived cytokine that induces differentiation and activation of type 2 helper T cells and innate lymphoid cells, cardinal effectors in pathophysiology of AD. We previously reported that ΔNp63, a p53-related molecule, regulates the expression of TSLP receptors and suggested the entity of a potential TSLP autocrine loop in the AD epidermis. In this study, we further explored the significance of p53 family transcription factors in TSLP production from human keratinocytes. METHOD Expression profile of p73, a p53-related molecule, was evaluated in human AD tissue by immunohistochemistry. In addition, the function of p73 in producing TSLP was investigated with in vitro cultured keratinocytes via molecular biological analysis. RESULTS ΔNp73 was abundantly expressed in the AD epidermis and increased the release of TSLP via NF-κB activation. Furthermore, the Toll-like receptor 3 signal enhanced ΔNp73 expression and thereby induced TSLP expression. CONCLUSION Our results indicate that ΔNp73 is an additional participant in the mechanism of TSLP production. Amending the aberrant state of keratinocytes, represented by overexpression of ΔNp73, can be a novel therapeutic target of AD.

Clinical and epidemiological analysis in 149 cases of rhododendrol-induced leukoderma

Rhododendrol‐induced leukoderma is an acquired depigmentation that develops mainly at the contact site after repeated use of skin‐whitening cosmetics containing rhododendrol. In most cases, cessation of further depigmentation or occurrence of repigmentation is observed after discontinuing the use of cosmetics. However, some patients develop vitiligo vulgaris through the spread of depigmentation into the non‐exposed areas. Our study aims to investigate the patient‐specific factors that may affect the extent of depigmentation or repigmentation, as well as development of vitiligo vulgaris. The degree of depigmentation of the face, neck and hands where exposed to rhododendrol was scored using photographs over time. The relationships between depigmentation score at first visit/improvement rate of depigmentation score and patient demographics were evaluated and three important clinical observations were made. First, repigmentation of the face was superior compared with that of the hands and neck, suggesting a possible role for the migration and differentiation of melanocyte stem cells from hair follicles, as a mechanism of repigmentation. Second, the intensity of rhododendrol exposure did not contribute to differences in the severity of depigmentation. This suggested a possibility of underlying genetic susceptibility to melanocyte cytotoxicity or immune reaction. Third, depigmentation score at first visit and past history of atopic dermatitis were significantly high in patients who developed vitiligo vulgaris. This suggested that severe chemical damage of melanocytes by rhododendrol leads to a higher risk of developing vitiligo vulgaris through the possible involvement of an immune reaction. These clinical observations may help to further understand the pathogenesis of rhododendrol‐induced leukoderma.

Serum cytokeratin 19 fragment 21‐1 is a useful tumor marker for the assessment of extramammary Paget's disease

Cytokeratin 19 fragment 21‐1 (CYFRA 21‐1) has been used as a tumor marker for several malignancies. However, to date, no studies have assessed whether CYFRA 21‐1 could be a useful marker for extramammary Pagets disease (EMPD). The present study aimed to evaluate the significance of CYFRA 21‐1 as a serum tumor marker for EMPD progression. Concentrations of serum CYFRA 21‐1 and carcinoembryonic antigen (CEA) in 13 cases of EMPD were measured prior to undergoing treatment at Sapporo Medical University Hospital from January 2014 to May 2016. Four of the 13 patients had lymph node metastases at diagnosis, but none had distant metastases. Immunohistochemistry indicated that all 13 primary tumors and four metastatic tumors in lymph nodes were positive for cytokeratin 19. Although none of the 13 patients showed high serum CEA levels, six patients (46.2%) had elevated serum CYFRA 21‐1. Furthermore, CYFRA 21‐1 was reduced in association with post‐treatment tumor reduction in all six patients. Among these six patients, four developed recurrence and metastasis during the follow‐up period. CYFRA 21‐1 was re‐elevated in all four of these patients; however, serum CEA was elevated only in the patient with distant metastasis. These results suggest that CYFRA 21‐1 is more sensitive compared with CEA, and can be useful as a tumor marker for evaluating tumor progression and treatment efficacy in patients with EMPD.

Biochemical effects of the flavanol-rich lychee fruit extract on the melanin biosynthesis and reactive oxygen species

An ingredient of fruit polyphenol, resveratrol, is known to have an inhibitory effect on melanogenesis. In order to examine the functional differences between resveratrol and other fruit polyphenols, we compared biochemical effects of a resveratrol‐free polyphenol, flavanol‐rich lychee fruit extract (FRLFE), with other phenolic compounds including resveratrol. FRLFE as well as hydroquinone and resveratrol suppressed growth of B16F1 melanoma cells more significantly than rhododendrol or arbutin. Resveratrol suppressed mushroom tyrosinase at the lowest concentration (23.0 μmol/L) among the compounds tested. FRLFE and hydroquinone suppressed tyrosinase at almost the same concentration (half maximal inhibitory concentration [IC50], 83.5 and 94.6 μmol/L, respectively), which was higher than rhododendrol, ascorbic acid and arbutin (IC50, 245, 345 and 421 μmol/L, respectively). Western blot analysis revealed that although resveratrol decreased expressions of tyrosinase and tyrosinase‐related protein 1, FRLFE did not affect their expressions. Both FRLFE and resveratrol suppressed antimycin A‐mediated reactive oxygen species (ROS) production in melanocytic cells. Resveratrol‐mediated ROS suppression was inhibited by nicotinamide, a SIRT1 inhibitor. However, FRLFE‐mediated suppression was not affected by nicotinamide. Moreover, FRLFE directly decreased superoxide in vitro, as detected by superoxide dismutase‐like scavenging activity assay. These results suggest that FRLFE can protect melanocytes from cytotoxicity caused by an excess amount of melanin and ROS in a different manner from resveratrol.

Successful treatment of pityriasis rubra pilaris with oral Vitamin A in oil (Chocola A®) for an 18-month-old child

Dear Editor, Pityriasis rubra pilaris (PRP) is a rare inflammatory keratosis, and many different therapeutic approaches have been employed for its treatment. However, few case reports on the use of vitamin A therapy for the treatment of PRP have been published. Additionally, the effective dose of vitamin A for the treatment of PRP has not been specifically mentioned, and the treatment duration is not clear. Here, we report the case of a Japanese girl with PRP, who was successfully treated with vitamin A therapy. An 18-month-old Japanese girl (weight, 10.1 kg) presented with progressive erythroderma and itchiness. Her palmar and plantar surfaces were hyperkeratotic with an orange hue and were fissured (Fig. 1a–c). She had no familial history of PRP. Histopathological analysis of a biopsy specimen obtained from a reddish plaque on her knee showed hyperkeratosis, alternating orthokeratosis and parakeratosis, and hypergranulosis in the epidermis (Fig. 1d). A sparse lymphocytic infiltrate with predominant perivascular distribution was observed in the upper dermis (Fig. 1e). She was subsequently diagnosed with classical type III PRP. Previous treatments included a topical steroid and maxacalcitol but neither proved effective. The skin lesions gradually expanded and covered the whole trunk; therefore, an oral retinyl palmitate in oil (Chocola A ; Vitamin A Oil, Tokyo, Japan) was administrated. At the start of the Chocola A therapy, her vitamin A levels were low (73 ng/mL). Initially, she was administrated 20 000 units of Chocola A daily. This dose proved ineffective at raising her vitamin A levels, and after 2 months, the dose was increased to 50 000 units. However, even after receiving this high dose daily for 3 months, she showed only a limited response to the therapy. The dose of Chocola A was then increased to 60 000 units, and after 2 months, clinical remission was achieved (Fig. 1f,g). At 111 ng/mL, her vitamin A levels were within the normal range (83–200 ng/mL). Even after remission, she was administrated 60 000 units of Chocola A. The patient did not experience any side-effects from the Chocola A therapy. Her condition greatly improved with the therapy, and the therapy was eventually discontinued. According to previous reports, retinoids should be used with caution, as spontaneous resolution occurs in up to 80% of cases. PRP has been successfully treated with retinoid doses ranging 0.5–2.13 mg/kg per day, and these doses reflect 500–2130 IU/kg per day vitamin A for Chocola A. Additionally, retinoid treatment durations were 16–24 weeks, with a typical response seen in 14–16 weeks.

Epidemiology of Childhood AD in Asian Countries

There have been many reported studies regarding the prevalence of childhood atopic dermatitis in Asia. The first large-scale worldwide investigation was the ISAAC Phase I study reported by Williams et al., who reported that the prevalence of atopic dermatitis in Asian countries, except for Japan, is lower than that of European countries. Moreover, they showed that symptoms of atopic eczema exhibit wide variations in prevalence both within and between countries inhabited by similar ethnic groups; they thus suggested that environmental factors may be critical for disease expression. These factors may be partially explained by “hygiene hypothesis,” which suggests that infections, especially during childhood, can protect against allergic diseases. This indicates that the clean environment in developed countries promotes the increase of allergic diseases such as atopic dermatitis.

Detection of human papillomavirus type 124 in a viral wart located on a thigh

with salicylic acid. Nilotinib preferentially inhibits the BCR-ABL tyrosine kinase but has also been shown to interact with the discoidin domain receptors, platelet-derived growth factor receptor and c-kit receptor. Although the mechanism underlying the keratosis pilaris-like eruptions that occur in response to nilotinib is largely unknown, nilotinib may modulate the tyrosine kinase receptor in hair follicles. On the other hand, keratosis pilarislike eruptions in response to RAF inhibitor, vemurafenib and dabrafenib have also been reported. The extracellular signalregulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway in wild-type BRAF melanoma cells was reported to be paradoxically activated by vemurafenib. Furthermore, nilotinib has been reported to possess weak “off target” activity against RAF protein in vitro. The common ERK/MAPK pathway may be involved in the pathogenesis of the vemurafeniband nilotinib-induced keratosis pilaris-like eruptions. Topical ointments, including retinoids, urea and salicylic acid, have been tried to treat generalized keratosis pilarislike eruptions, but the clinical effectiveness is variable. The clinical manifestation of keratosis pilaris-like eruption due to TKI may be rare and variable, and clinicians should keep the condition in mind. CONFLICT OF INTEREST: None declared.

Severe atopic dermatitis associated with transient hypogammaglobulinemia of infancy

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