We have demonstrated that cytokine thymic stromal lymphopoietin (TSLP), whose expression is rapidly induced upon keratinocyteselective ablation of retinoid X receptors (RXRs) -␣ and -␤ in the mouse (RXR␣␤ ep؊/؊ mice), plays a key role in initiating a skin and systemic atopic dermatitis-like phenotype. We show here that topical application of the physiologically active ligand [1␣,25-(OH) 2D3; calcitriol] of the vitamin D receptor, or of its low-calcemic analog MC903 (calcipotriol; Dovonex), induces TSLP expression in epidermal keratinocytes, which results in an atopic dermatitis-like syndrome mimicking that seen in RXR␣␤ ep؊/؊ mutants and transgenic mice overexpressing TSLP in keratinocytes. Furthermore, topical application of retinoic acid receptor RAR␥-selective agonist BMS961 also induces TSLP expression either on its own or synergistically with 1␣,25-(OH)2D3. Our data demonstrate that RXR͞ vitamin D receptor and RXR͞retinoic acid receptor-␥ heterodimers and their ligands cell-autonomously control the expression of TSLP in epidermal keratinocytes of the mouse. We propose molecular mechanisms through which vitamin D3 and retinoic acid signalings could be involved in the pathogenesis of atopic diseases.retinoic acid ͉ vitamin D receptor ͉ retinoid X receptor ͉ retinoic acid receptor ͉ skin N uclear receptors (NRs) belong to a superfamily of liganddependent transcriptional regulators (1, 2). Within this superfamily, retinoid X receptors (RXRs) -␣, -␤, and -␥ play a key role through heterodimerization with some 15 NR partners, e.g., retinoic acid receptors (RARs), vitamin D receptor (VDR), peroxisome proliferator-activated receptors, and liver X receptors (1, 2). We reported (3) that selective ablation of RXR␣ and RXR␤ in adult mouse epidermal keratinocytes (RXR␣␤ epϪ/Ϫ mice) triggers a skin and systemic syndrome similar to human atopic dermatitis (AD), a chronic skin inflammatory disease with a strong genetic component that affects children (10-20%) and adults (1-3%) (4). These mice exhibit the major features of the human AD syndrome that include (i) skin eczematous-like lesions with xerosis and pruritus, associated with a skin inflammatory infiltrate mainly composed of CD4 ϩ T helper (Th) type 2 cells, dendritic cells, eosinophils, and mast cells and (ii) systemic abnormalities, including elevated serum IgE and IgG levels and blood and tissue eosinophilia.We found that expression of the cytokine thymic stromal lymphopoietin (TSLP), known to be produced in epidermal keratinocytes of AD patients (5), is rapidly induced in keratinocytes of RXR␣␤ epϪ/Ϫ mice. Furthermore, we showed that K14-TSLP transgenic mice overexpressing TSLP in keratinocytes exhibit an ADlike phenotype similar to that of RXR␣␤ epϪ/Ϫ mice (3), demonstrating that TSLP can act as an initiating cytokine at the top of a chain of immunological events that lead to an AD-like phenotype, in keeping with other recent studies on mouse models of human allergic inflammatory diseases (asthma and AD) (6-9).We suggested that up-regulation of keratinocytic TSLP...

Understanding molecular mechanisms for regeneration of hair follicles provides new opportunities for developing treatments for hair loss and other skin disorders. Here we show that fibroblast growth factor 9 (Fgf9), initially secreted by γδ T cells, modulates hair follicle regeneration after wounding the skin of adult mice. Reducing Fgf9 expression decreases this wound-induced hair neogenesis (WIHN). Conversely, overexpression of Fgf9 results in a two- to threefold increase in the number of neogenic hair follicles. We found that Fgf9 from γδ T cells triggers Wnt expression and subsequent Wnt activation in wound fibroblasts. Through a unique feedback mechanism, activated fibroblasts then express Fgf9, thus amplifying Wnt activity throughout the wound dermis during a crucial phase of skin regeneration. Notably, humans lack a robust population of resident dermal γδ T cells, potentially explaining their inability to regenerate hair after wounding. These findings highlight the essential relationship between the immune system and tissue regeneration. The importance of Fgf9 in hair follicle regeneration suggests that it could be used therapeutically in humans.

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Atopic dermatitis (AD) is often the initial step in the ''atopic march,'' given that more than half of AD patients with moderate to severe AD develop asthma later in life. Both AD and asthma share a similar ''atopy'' phenotype that includes T helper type 2 inflammation with eosinophilia and hyper-IgE immunoglobulinemia, but the molecular mechanisms underlying the ''atopic march'' remain elusive. In the present study, we show that induced expression of thymic stromal lymphopoietin (TSLP) in mouse epidermal keratinocytes upon topical application of MC903 (a low calcemic analogue of vitamin D3) not only triggers AD as we previously reported but also aggravates experimental allergic asthma induced by ovalbumin sensitization and challenge. Our study, which provides a mouse model to study human ''atopic march,'' indicates that keratinocyte-produced TSLP may represent an important factor in the link of atopic dermatitis to asthma.A topic dermatitis (AD) is a common skin disease that is often associated with other atopic disorders, such as asthma and allergic rhinitis. AD, characterized by pruritic and eczematoid skin lesions, affects children (10%-20%) and adults (1%-3%) (1, 2). Asthma is a chronic airway inflammatory disease, exhibiting lung allergic inflammation, mucus hypersecretion, and airway hyperreactivity (AHR) (3, 4). Epidemiologic analysis shows that AD is often the initial step in the so-called ''atopic march'' (1, 5-7), given that more than 50% of AD patients with moderate to severe AD develop asthma later in life, and the severity of AD influences the course of respiratory allergy. Both AD and asthma share an ''atopy'' phenotype that includes a T helper type 2 (Th2) inflammation with eosinophilia and hyper-IgE immunoglobulinemia (5, 6), but the molecular mechanisms underlying the ''atopic march'' remain unclear.Recently, thymic stromal lymphopoietin (TSLP) emerged as a likely master regulator of AD inflammation (8-10). Overproduction of TSLP was found in keratinocytes of human AD skin lesions (11). We reported that selective ablation of retinoid X receptors (RXRs) in epidermal keratinocytes in adult mice induces TSLP expression in epidermis and triggers an AD-like syndrome (12). Our study (12) and a study by Yoo et al. (13) demonstrated that mice overexpressing TSLP in keratinocytes developed a similar AD-like dermatitis. More recently, we showed that topical application of MC903 (calcipotriol; a low-calcemic analogue of vitamin D3) (14) triggers an AD-like syndrome through the induction of keratinocytic TSLP expression (15,16). On the basis of these results, which indicate that TSLP is both sufficient and necessary in triggering an AD inflammation, and the fact that asthma is often associated with AD, we speculated that the occurrence of asthma may be increased in mice exhibiting TSLP-induced AD.To investigate this possibility, mice topically treated with MC903 (16) were subjected to an ovalbumin (OVA)-induced asthma protocol, in which OVA sensitization and intranasal challenge induce characteristic feat...

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degranulation, and mediator release of human MCs in vitro, and that topical treatment with a 6% miltefosine solution may inhibit IgE-dependent human MC activation in vivo. The in vitro MCstabilizing effect of miltefosine appears not to be limited to IgE-dependent activation nor to histamine release but also comprises alternative IgE-independent activation pathways and release of cytokines. In addition, we provide proof-of-concept that miltefosine also inhibits IgE-dependent MC-mediated inflammatory responses in vivo.These results indicate that agents with raft disrupting properties, such as miltefosine, have the potential as new therapeutics for the treatment of MC-driven diseases and we suggest that clinical studies should be undertaken to confirm the efficacy of miltefosine and related substances on MC-related effects. In addition, future investigations will need to address the complexity of cellular pathways involved in their inhibition of MC activation and mediator release. All examinations were performed after institutional approval and in adherence to the Declaration of Helsinki. All volunteers gave their written informed consent.

Long noncoding RNAs (lncRNAs) have recently emerged as pivotal regulators in governing fundamental biological processes, as well as in tumorigenesis. The nuclear paraspeckle assembly transcript 1 (NEAT1) is one of the most highly regulated lncRNAs in recent genomic datasets, however, its biological role and regulatory mechanism in ovarian cancer (OC) development and progression are poorly defined. In this study, we identified that NEAT1 was up‐regulated in OC patients and cell lines, and its expression was associated with the FIGO stage and lymph node metastasis. Furthermore, the ectopic expression of NEAT1_1 in OVCAR‐3 cell lines promoted cell proliferation and invasion, whereas knockdown of NEAT1_1 did the opposite. Furthermore, NEAT1_1 was stabilized by an RNA‐binding protein HuR, but suppressed by miR‐124‐3p in OC cells. Accordingly, the increased HuR mRNA and decreased miR‐124‐3p levels were observed in OC patients. These results suggested that lncRNA NEAT1, whose expression was collaboratively controlled by HuR and miR‐124‐3p, could regulate ovarian carcinogenesis and may serve as a potential target for antineoplastic therapies.

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