Erythroid differentiation regulator (Erdr1) was first discovered in mouse leukemia cell lines and functions as a stress-related survival factor. This study investigated whether Erdr1 regulates murine melanoma progression, as well as the mechanism involved in Erdr1-regulated metastasis. The expression of Erdr1 is negatively correlated with IL-18 expression, which has a pro-cancer effect in melanoma. To study the role of Erdr1 as an anti-cancer factor, cell migration, invasion, and proliferation were measured. Erdr1 overexpression markedly inhibited the level of cell migration, invasion, and proliferation in B16F10 cells in vitro. In addition, Erdr1 overexpression significantly suppressed melanoma lung colonization, metastasis, and tumor growth in vivo. To identify the factors involved in Erdr1-reduced metastasis, heat shock protein 90 (HSP90), a well-known stress protein and contributor to tumor metastasis, was examined. We found that HSP90 was significantly decreased in Erdr1-overexpressing cells. Functional analysis demonstrated that HSP90 small-interfering RNA transfection reduced the migration ability and metastasis of melanoma. In conclusion, Erdr1 shows a powerful anti-metastasis effect that leads to the ability to reduce the metastatic potential of murine malignant melanoma cells. Erdr1 is an anti-metastatic factor that may be a possible therapeutic target for treatment of melanoma.

Propionibacterium acnes (P. acnes) is a well-known acne-inducing factor which causes inflammatory skin lesions by enhancing cytokine production through toll-like receptor 2 (TLR2). Green tea extract catechin has been documented to possess anti-inflammatory effects. However, little is known about the mechanisms involved or any direct effect of green tea catechin on acne. The present study investigated the therapeutic effects and mechanism of polyphenon-60, also known as green tea catechin compound, on acne in vitro and in vivo. In a clinical study using topical polyphenon-60 treatment, acne patients showed symptomatic improvement with decrease in the number of comedos and pustules. To investigate the mechanism underlying the activity of polyphenon-60 in acne therapy, an in vitro study was performed. We found that polyphenon-60 reduced the levels of P. acnes-enhanced TLR2 and interleukin-8 (IL-8) in THP-1 cells, human monocyte cell line and human primary monocytes. Taken together, these data demonstrate that polyphenon-60 has a therapeutic effect on acne by suppressing inflammation, specifically by inhibiting TLR2 expression and IL-8 secretion via down-regulation of extracellular signal-regulated kinases 1/2 (ERK1/2) pathway and activator protein-1 (AP-1) pathway.

c.474G>A, was considered to be responsible for the milder phenotype in our patient.Our RT-PCR for c.474G>A detected three transcripts, including two out-of-frame transcripts and an in-frame transcript. The inframe transcript displayed expression level equivalent to that of normal protein.In conclusion, we found that c.474G>A synonymous mutation causes abnormal splicing, and the in-frame mutant transcript accounts for the mild phenotype in our patient. The results further expanded the mutation spectrum in NS and demonstrated the importance of RNA analysis to precisely understand molecular basis of genodermatosis. AcknowledgementsSee Data S2 for details. Author contributionsS.N. and T.H. (Hamada) designed the study. S.N. and K.T. performed the study and analysed the data. Y.O, K.H and M.M. gave clinical and pathological information. P.F., GD.Z, DC and G.Z. provided the antibodies against the D7-12 and D14-15 of LEKTI. RP.K helped to make figures. S.N., K.T. and T.H (Hashimoto) wrote the paper. Conflict of interestThe authors have declared no conflicting interests. Supporting InformationAdditional Supporting Information may be found online in the supporting information tab for this article:Data S1. Methods. BackgroundPsoriasis is a common chronic skin disease which is accompanied by chronic inflammation. Various proinflammatory cytokines including IL-18, TNF-a and IL-12, which are elevated in psoriatic lesional skin and have critical roles in psoriasis pathogenesis, have been identified and targeted for psoriasis treatment (1). In particular, IL-18 has been classified as a biomarker for psoriasis activity with other cytokines (2). It has been confirmed that serum IL-18 concentration and cutaneous IL-18 expression in the skin is significantly elevated in psoriasis patients, compared with normal healthy donors, and there is a positive correlation between serum IL-18 expression and the Psoriasis Area and Severity Index (PASI) (2,3). Questions addressedIn our previous studies, we found that erythroid differentiation regulator 1 (Erdr1) is negatively regulated by IL-18 in mouse melanoma, suggesting the opposite effects of Erdr1 with IL-18 (4). In this study, we investigated whether Erdr1 is negatively regulated by IL-18 in human keratinocytes and evaluated the downregulation of Erdr1 in psoriasis to determine whether Erdr1 acts as a novel regulator for psoriasis pathogenesis. Methods Letter to the Editor Experimental designFor full details of materials and methods, see Data S1. ResultsTo determine whether Erdr1 expression has an inverse correlation with IL-18 expression in keratinocytes, HaCaT cells were transfected with IL-18 siRNA or negative siRNA. The relative Erdr1 expression level is significantly higher in IL-18 siRNA transfectants incubated for 48 h than in IL-18 siRNA transfectants incubated for 24 h, showing much more increase of Erdr1 in accordance with more decrease of IL-18 (Fig. 1a, b). Densitometry data show approximately a twofold increase in Erdr1 expression after IL-18 siRNA transfection, indicating ...

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease, and multiple inflammatory cytokines are involved in RA pathogenesis. Interleukin (IL)-18, in particular, has a significant positive correlation with RA. In this study, we investigated the effect of erythroid differentiation regulator 1 (Erdr1), which is negatively regulated by IL-18, in an animal model of inflammatory arthritis, collagen-induced arthritis (CIA) in DBA/1J mice. Treatment of mice with recombinant (r)Erdr1 significantly suppressed the severity of arthritis, histologic features of arthritic tissue, and serum levels of anti-collagen autoantibodies (IgG, IgG1, IgG2a and IgM) in CIA. In addition, IL-18 expression was reduced in the affected synovium of rErdr1-treated mice. Interestingly, Erdr1 treatment suppressed migration in contrast to the pro-migratory effect of IL-18, indicating the therapeutic effects of Erdr1 on CIA through inhibiting synovial fibroblast migration. In addition, Erdr1 inhibited activation of ERK1/2, a key signaling pathway in migration of various cell types. Taken together, these data show that rErdr1 exerts therapeutic effects on RA by inhibiting synovial fibroblast migration, suggesting that rErdr1 treatment might be an effective therapeutic approach for RA.

Interleukin (IL)-32α, the shortest isoform of proinflammatory cytokine IL-32, is associated with various inflammatory diseases and cancers. However, its involvement in human melanoma is not understood. To determine the effect of IL-32α in melanoma, IL-32α levels were examined in human melanoma cell lines that exhibit different migratory abilities. IL-32α levels were higher in human melanoma cell lines with more migratory ability. An IL-32α-overexpressing G361 human melanoma cell line was generated to investigate the effect of IL-32α on melanoma migration. IL-32α-overexpressing G361 cells (G361-IL-32α) exhibit an increased migratory ability compared to vector control cells (G361-vector). To identify factors involved in IL-32α-induced migration, we compared expression of E-cadherin in G361-vector and G361-IL-32α cells. We observed decreased levels of E-cadherin in G361-IL-32α cells, resulting in F-actin polymerization. To further investigate signaling pathways related to IL-32α-induced migration, we treated G361-vector and G361-IL-32α cells with PD98059, a selective MEK inhibitor. Inhibition of Erk1/2 by PD98059 restored E-cadherin expression and decreased IL-32α-induced migration. In addition, cell invasiveness of G361-IL-32α cells was tested using an in vivo lung metastasis model. As results, lung metastasis was significantly increased by IL-32α overexpression. Taken together, these data indicate that IL-32α induced human melanoma migration via Erk1/2 activation, which repressed E-cadherin expression. Our findings suggest that IL-32α is a novel regulator of migration in melanoma.