Sayaka Hayashida

Periostin promotes chronic allergic inflammation in response to Th2 cytokines

Allergic inflammation triggered by exposure of an allergen frequently leads to the onset of chronic inflammatory diseases such as atopic dermatitis (AD) and bronchial asthma. The mechanisms underlying chronicity in allergic inflammation remain unresolved. Periostin, a recently characterized matricellular protein, interacts with several cell surface integrin molecules, providing signals for tissue development and remodeling. Here we show that periostin is a critical mediator for the amplification and persistence of allergic inflammation using a mouse model of skin inflammation. Th2 cytokines IL-4 and IL-13 stimulated fibroblasts to produce periostin, which interacted with αv integrin, a functional periostin receptor on keratinocytes, inducing production of proinflammatory cytokines, which consequently accelerated Th2-type immune responses. Accordingly, inhibition of periostin or αv integrin prevented the development or progression of allergen-induced skin inflammation. Thus, periostin sets up a vicious circle that links Th2-type immune responses to keratinocyte activation and plays a critical role in the amplification and chronicity of allergic skin inflammation.

Decrease in circulating Th17 cells correlates with increased levels of CCL17, IgE and eosinophils in atopic dermatitis

BACKGROUND Clinical significance of circulating CD4(+) T cell subsets, including T-helper (Th)1, Th2, Th17 and regulatory T (Treg) cells, in patients with atopic dermatitis (AD) remains unclear. No previous studies have simultaneously evaluated the four T cell subset profiles in AD. OBJECTIVE The aim of the present study was to explore whether the percentage of these four subsets of CD4(+) T cells correlate to the severity parameters of AD patients. METHODS Intracellular expression of interferon (IFN)-γ, interleukin (IL)-4, IL-17 and forkhead box P3 (Foxp3) in CD4(+) T cells was evaluated in peripheral blood mononuclear cells from normal controls and patient with AD as well as with chronic eczema using a flow cytometer. Serum CCL17 levels were measured as an objective severity parameter of AD together with percentage of eosinophils and serum IgE levels. RESULTS In AD patients, the number of Th1 (IFN-γ(+)) and Th17 (IL-17(+)) subsets was significantly decreased, but that of Th2 (IL-4(+)) and Treg (Foxp3(+)) subsets was similar to that of normal controls. The T cell subset profiles of patients with chronic eczema were not different with those of normal controls. The frequency of Th17cells, particularly that of the IFN-γ(nega)IL-17(+) subset, showed a significant negative correlation with CCL17, IgE and eosinophil levels in AD patients. This was, however, not the case in Th1, Th2 and Treg cells. CONCLUSION Decreased circulating Th17 cells might contribute to activity of AD.

Are lifetime prevalence of impetigo, molluscum and herpes infection really increased in children having atopic dermatitis?

BACKGROUND Cutaneous infections such as impetigo contagiosum (IC), molluscum contagiosum (MC) and herpes virus infection (HI) appear to be associated with atopic dermatitis (AD), but there are no reports of concrete epidemiological evidence. OBJECTIVE We evaluated the association of childhood AD with these infections by conducting a population-based cross-sectional study. METHODS Enrolled in this study were 1117 children aged 0-6 years old attending nursery schools in Ishigaki City, Okinawa Prefecture, Japan. Physical examination was performed by dermatologists, and a questionnaire was completed on each childs history of allergic diseases including AD, asthma, allergic rhinitis and egg allergy, and that of skin infections including IC, MC and HI, as well as familial history of AD. RESULTS In 913 children (AD; 132), a history of IC, MC or HI was observed in 45.1%, 19.7%, and 2.5%, respectively. Multiple logistic regression analysis revealed that the odds of having a history of IC were 1.8 times higher in AD children than in non-AD children. Meanwhile, a history of MC was significantly correlated to the male gender, but not to a personal history of AD. As for HI, we found no correlated factors in this study. CONCLUSIONS The lifetime prevalence of IC was indeed higher in young children with a history of AD.

Differential expression of phosphorylated extracellular signal-regulated kinase 1/2, phosphorylated p38 mitogen-activated protein kinase and nuclear factor-κB p105/p50 in chronic inflammatory skin diseases

The keratinocytes actively participate in the cutaneous immune responses. Dysregulation and abnormal expression of inflammatory mediators or their receptors in keratinocytes are relevant to the pathogenesis of chronic inflammatory skin diseases. The mechanism of long‐lasting inflammatory processes is related with the activation of nuclear factor (NF)‐κB and mitogen‐activated protein kinase (MAPK), which play a crucial role in the immune responses. There are potential interaction points between these two pathways. The aim of this study is to investigate the differences in expression levels and distributions of phosphorylated extracellular signal‐regulated kinase (ERK)1/2, phosphorylated p38 MAPK and NF‐κB p105/p50 in chronic inflammatory skin diseases. An immunohistochemical staining technique was employed to measure the expression of these molecules in 25 cases of lichen planus, 22 cases of psoriasis, 26 cases of chronic eczema, seven cases of prurigo and seven cases of normal skin. We observed that the expression of phosphorylated ERK1/2, phosphorylated p38 MAPK and NF‐κB p105/p50 was significantly more augmented in the lesional epidermis of all the inflammatory skin diseases than those in normal skin (P < 0.05), and the number of positive keratinocytes was significantly more in lichen planus than that in other inflammatory diseases (P < 0.001). Moreover, the positive keratinocytes of these three molecules were more widely distributed in the entire layer of the epidermis in lichen planus than those in other diseases. We concluded that ERK1/2, p38 MAPK and NF‐κB p105/p50 might play important roles in the pathophysiology of chronic inflammatory skin diseases.

Overexpression of phosphorylated‐ATF2 and STAT3 in cutaneous angiosarcoma and pyogenic granuloma

Background:  Activating transcription factor‐2/Activator protein‐1 (AP‐1), Signal transducer and activator of transcription‐3 and p53 are important regulators of cellular proliferation, apoptosis, differentiation in the pathogenesis of many human tumors, but the expression of phosphorylated (p)‐activating transcription factor‐2 (p‐ATF2), phosphorylated (p)‐signal transducer and activator of transcription‐3 (p‐STAT3) and p53 family (p63 and p73) has not been investigated in cutaneous angiosarcoma (CAS) and pyogenic granuloma (PG) so far.

Expression of CD10 predicts tumor progression and unfavorable prognosis in malignant melanoma

BACKGROUND CD10 expression in malignant melanoma (MM) has been reported to increase according to tumor progression and metastasis; however, its association with patient outcome has not been clarified. OBJECTIVE We examined the immunohistochemical expression of CD10 in MM to determine whether or not it could serve as a marker for tumor progression and prognosis. METHODS A total of 64 formalin-fixed, paraffin-embedded samples of primary MM were immunostained for CD10. Similarly, 40 samples of melanocytic nevus and 20 of metastatic MM were analyzed for comparison. The following clinicopathologic variables were evaluated: age, gender, histologic type, tumor site, Breslow thickness, Clark level, the presence or absence of ulceration and tumor-infiltrating lymphocytes, and survival. Statistical analyses were performed to assess for associations. Several parameters were analyzed for survival using the Kaplan-Meier method and Cox proportional hazards model. RESULTS Immunohistochemical analysis revealed that 34 of 64 cases (53%) of primary MM expressed CD10, compared with 15 of 20 cases (75%) of metastatic MM and only 4 of 40 cases (10%) of nevus. There was a significant positive relationship between CD10 expression and Breslow thickness, Clark level, and ulceration. Univariate analysis revealed 4 significant factors for shorter survival periods: CD10 expression, high Breslow thickness, high Clark level, and the presence of ulceration (P < .01 each). In multivariate analysis, CD10 expression was revealed to be a statistically significant and independent prognostic factor. LIMITATIONS The major limitation was the small sample size. CONCLUSION CD10 expression may serve as a progression marker and can predict unfavorable prognosis in patients with MM.

Differential expression of two new members of the p53 family, p63 and p73, in extramammary Paget's disease

Background.  The proteins p53, p63 and p73 are known to be overexpressed and to play important roles in the pathogenesis of many tumours, but the expression of p63 and p73 has not previously been investigated in extramammary Paget’s disease (EMPD).

Cathepsin K-upregulation in fibroblasts promotes matrigel invasive ability of squamous cell carcinoma cells via tumor-derived IL-1α

BACKGROUND Cathepsin K (CTSK), a cysteine protease with strong collagenolytic properties, is involved in extracellular matrix turnover. In the previous studies, CTSK expression was detected in peritumoral fibroblasts (Fbs) around squamous cell carcinoma (SCC), but not in those surrounding benign epidermal tumors. However, the mechanism governing CTSK expression in epidermal tumors remains unclear. OBJECTIVE To study the regulatory mechanisms of fibroblastic CTSK expression in the SCC-stromal interaction. METHODS We examined dynamic interactions of Fbs with tumorigenic SCC cells (A431 and A253) or normal human keratinocytes. RESULTS SCC cells and normal keratinocytes did not synthesize CTSK, while Fbs constitutively expressed CTSK. When cocultured, SCC cells upregulated fibroblastic CTSK expression more potently than did normal keratinocytes, which was mainly attributable to SCC-derived IL-1α. Coculturing Fbs with SCC cells significantly augmented the matrigel invasive ability of SCC cells, which was downregulated when cocultured with CTSK knockdown Fbs or in the presence of neutralizing anti-IL-1α antibody. CONCLUSION The CTSK-upregulated Fbs generated by SCC-derived IL-1α may play a crucial role in the progression and invasion of SCC.

Assessment of abnormal blood flow and efficacy of treatment in patients with systemic sclerosis using a newly developed microwireless laser Doppler flowmeter and arm‐raising test

Background  Patients with systemic sclerosis (SSc) frequently suffer from recalcitrant digital ulceration because of impaired cutaneous blood flow (CBF). A simple and accurate CBF measurement would be helpful to evaluate the disease status and efficacy of treatment in such patients.

Scratching behavior does not necessarily correlate with epidermal nerve fiber sprouting or inflammatory cell infiltration.

BACKGROUND Increased sprouting of epidermal nerve fibers of lesional skin are thought to be associated with persistent pruritus in chronic inflammatory dermatitis such as atopic dermatitis as supported by a murine study using tacrolimus (or FK506: FK) which was shown to inhibit both epidermal sprouting of nerves and scratching behavior or by immunohistochemical observations of lesional skin in the patients with atopic dermatitis or prurigo, etc. OBJECTIVES To examine a mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 (MEK1/2) inhibitor (CX-659S: CX) for a possible anti-pruritic property in vivo since some MEK1/2 inhibitors have been reported to inhibit neurite growth in vitro. METHODS CX, FK and corticosteroids (betamethasone valerate: BV) were topically applied on inflamed skin in a mouse model of chronic dermatitis using repetitive hapten painting to examine anti-pruritic property and anti-inflammatory effects. Scratching behaviors were assessed using MicroAct automatic measuring system, and epidermal sprouting of nerves and skin inflammation was assessed histologically. RESULTS FK significantly decrease scratching behavior, but CX and BV failed to do so despite of their ability to significantly inhibit epidermal nerve fiber sprouting and skin inflammation, respectively. In addition, CX+BV mixture synergistically inhibited epidermal nerve fiber sprouting and skin inflammation even more potently than FK without decreasing scratching behavior. CONCLUSIONS These findings suggest that the scratching behavior does not necessarily correlate with epidermal nerve fiber sprouting or inflammatory cell infiltration.