Tomoya Watanabe

Decreased Expression of Caveolin-1 Contributes to the Pathogenesis of Psoriasiform Dermatitis in Mice

Psoriasis is a chronic inflammatory skin disease characterized by excessive proliferation and abnormal keratinocyte development, in which T helper type 17 cells and signal transducer and activator of transcription 3 (STAT3) activation have pivotal roles. Moreover, caveolin-1 (CAV-1) has been implicated in the regulation of signal transduction, and aberrant CAV-1 expression is involved in a variety of diseases. However, whether CAV-1 is involved in psoriasis is unknown. Here we examined CAV-1 expression in the psoriatic epidermis and investigated its role in the pathogenesis of psoriasis. CAV-1 was markedly reduced in lesional epidermis of psoriasis patients. CAV1 silencing in keratinocytes in vitro revealed significant activation of STAT3, leading to increased expression of keratin 16 and several cytokine/chemokines, such as IL-6, C-X-C chemokine ligand 8 (CXCL8), CXCL9, and C-C chemokine ligand 20. In addition, psoriasis-related cytokines, including tumor necrosis factor-α (TNF-α), decreased CAV-1 expression in keratinocytes. Finally, administration of CAV-1 scaffolding domain peptide in a murine model of psoriasis-like skin inflammation induced by imiquimod improved the skin phenotype and reduced epidermal thickness and infiltrating cell counts. Furthermore, expression of TNF-α, IL-17A, and IL-23 was significantly suppressed by this treatment. Collectively, our study indicated that CAV-1 participates in the pathogenesis of psoriasis by regulating the STAT3 pathway and cytokine networks.

The Transcription Factor IRF8 Counteracts BCR-ABL to Rescue Dendritic Cell Development in Chronic Myelogenous Leukemia

BCR-ABL tyrosine kinase inhibitors (TKI) have dramatically improved therapy for chronic myelogenous leukemia (CML). However, several problems leading to TKI resistance still impede a complete cure of this disease. IFN regulatory factor-8 (IRF8) is a transcription factor essential for the development and functions of immune cells, including dendritic cells. Irf8(-/-) mice develop a CML-like disease and IRF8 expression is downregulated in patients with CML, suggesting that IRF8 is involved in the pathogenesis of CML. In this study, by using a murine CML model, we show that BCR-ABL strongly inhibits a generation of dendritic cells from an early stage of their differentiation in vivo, concomitant with suppression of Irf8 expression. Forced expression of IRF8 overrode BCR-ABL (both wild-type and T315I-mutated) to rescue dendritic cell development in vitro, indicating that the suppression of Irf8 causes dendritic cell deficiency. Gene expression profiling revealed that IRF8 restored the expression of a significant portion of BCR-ABL-dysregulated genes and predicted that BCR-ABL has immune-stimulatory potential. Indeed, IRF8-rescued BCR-ABL-expressing dendritic cells were capable of inducing CTLs more efficiently than control dendritic cells. Altogether, our findings suggest that IRF8 is an attractive target in next-generation therapies for CML.

The serum level of HMGB1 (high mobility group box 1 protein) is preferentially high in drug‐induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms

denominator of TEN development. A single or multiplier effect by idiosyncratic, dose-related or drug-interactive reactions of phytochemicals or contaminants might be involved in the development of TEN in these patients. The objective evaluation by the Naranjo adverse drug reaction (ADR) probability scale calculated a possible ADR by the herbal remedy in cases 1 and 3 and a probable cause in case 2. In all cases, the TEN-specific algorithm for epidermal necrolysis (ALDEN) confirmed a possible cause of herbal remedies in TEN developement.

Reduction of interleukin-10 production by B cells in intractable toxic epidermal necrolysis.

Several interleukin (IL)‐10 producing B‐cell subsets have been identified recently. However, few studies have examined the role of them in toxic epidermal necrolysis (TEN). We describe a 41‐year‐old woman with TEN who had B‐cell lymphoma and a history of treatments including B‐cell depletion therapy. Her re‐epithelization was still ongoing after 7 months, despite treatments. To investigate her immune system, we compared cytokine and chemokine production from B cells and non‐B cells isolated from the patient and another non‐lymphoma TEN patient. IL‐10 production from B cells decreased in the patient compared with the control TEN‐only patient. Cytokine and chemokine levels from non‐B cells involved in inflammation were elevated in the patient compared with the control patient. In conclusion, this study demonstrates that IL‐10 from B cells as well as regulatory T cells is critical in the pathogenesis of TEN, and that B‐cell dysfunction based on B‐cell lymphoma and B‐cell depletion therapy may be involved in the intractability of TEN.

Case of adult-onset verrucous hemangioma developed after repeated trauma.

Dear Editor, Verrucous hemangioma (VH) is an uncommon, congenital and vascular malformation. It is typically unilateral and localized to the lower extremities such as lower legs and back of foot. Typically, VH presents at birth or in early childhood. Here, we report a case of adult-onset VH in which trauma was considered as a cause. A 79-year-old man presented with a nodular lesion on his right lower leg. Clinical examination revealed a solitary blackish brown-colored nodule of 45 mm 9 30 mm in size on his right medial malleolus. The nodule was hard with a papillary surface (Fig. 1a). He had a history of frequent trauma at the same site by a left shoe with a spiked part when he took exercise in

Multiple fixed drug eruption caused by cyclophosphamide and its metabolite

ejd.2013.1953 Auteur(s) : Hiroyuki Fujita1 fuji_fuji_fuji_0101@yahoo.co.jp, Tomoya Watanabe1, Rika Okada1, Yuu Nozaki1, Motoko Ayabe1, Tomoyuki Imagawa2, Shunpei Yokota2, Michiko Aihara1 1 Department of Environmental Immuno-Dermatology, 2 Department of Pediatrics, Yokohama City University Graduate School of Medicine, Fukuura 3-9, Kanazawa, Yokohama, 236-0004, Japan Fixed drug eruption (FDE) is a cutaneous adverse drug reaction characterized by recurrence at the same skin or mucous membrane sites [...]