AESIS-1, a Rheumatoid Arthritis Therapeutic Peptide, Accelerates Wound Healing by Promoting Fibroblast Migration in a CXCR2-Dependent Manner.

In patients with autoimmune disorders such as rheumatoid arthritis (RA), delayed wound healing is often observed. Timely and effective wound healing is a crucial determinant of a patient's quality of life, and novel materials for skin wound repair, such as bioactive peptides, are continuously being studied and developed. One such bioactive peptide, AESIS-1, has been studied for its well-established anti-rheumatoid arthritis properties. In this study, we attempted to use the anti-RA material AESIS-1 as a therapeutic wound-healing agent based on disease-modifying antirheumatic drugs (DMARDs), which can help restore prompt wound healing. The efficacy of AESIS-1 in wound healing was assessed using a full-thickness excision model in diabetic mice; this is a well-established model for studying chronic wound repair. Initial observations revealed that mice treated with AESIS-1 exhibited significantly advanced wound repair compared with the control group. In vitro studies revealed that AESIS-1 increased the migration activity of human dermal fibroblasts (HDFs) without affecting proliferative activity. Moreover, increased HDF cell migration is mediated by upregulating chemokine receptor expression, such as that of CXC chemokine receptor 2 (CXCR2). The upregulation of CXCR2 through AESIS-1 treatment enhanced the chemotactic reactivity to CXCR2 ligands, including CXC motif ligand 8 (CXCL8). AESIS-1 directly activates the ERK and p38 mitogen-activated protein kinase (MAPK) signaling cascades, which regulate the migration and expression of CXCR2 in fibroblasts. Our results suggest that the AESIS-1 peptide is a strong wound-healing substance that increases the movement of fibroblasts and the expression of CXCR2 by turning on the ERK and p38 MAPK signaling cascades.

Erythroid Differentiation Regulator 1 Strengthens TCR Signaling by Enhancing PLCγ1 Signal Transduction Pathway.

Erythroid differentiation regulator 1 (Erdr1) has previously been reported to control thymocyte selection via TCR signal regulation, but the effect of Erdr1 as a TCR signaling modulator was not studied in peripheral T cells. In this report, it was determined whether Erdr1 affected TCR signaling strength in CD4 T cells. Results revealed that Erdr1 significantly enhanced the anti-TCR antibody-mediated activation and proliferation of T cells while failing to activate T cells in the absence of TCR stimulation. In addition, Erdr1 amplified Ca2+ influx and the phosphorylation of PLCγ1 in CD4 T cells with the TCR stimuli. Furthermore, NFAT1 translocation into nuclei in CD4 T cells was also significantly promoted by Erdr1 in the presence of TCR stimulation. Taken together, our results indicate that Erdr1 positively modulates TCR signaling strength via enhancing the PLCγ1/Ca2+/NFAT1 signal transduction pathway.

The Wound Healing Peptide, AES16-2M, Ameliorates Atopic Dermatitis In Vivo.

Peptide materials have recently been considered for use in various industrial fields. Because of their efficacy, safety, and low cost, therapeutic peptides are studied for various diseases, including atopic dermatitis (AD). AD is a common inflammatory skin disease impairing the patient's quality of life. Various therapies, such as treatments with corticosteroids, calcineurin inhibitors, and antibody drugs, have been applied, but numerous side effects have been reported, including skin atrophy, burning, and infection. In the case of antibody drugs, immunogenicity against the drugs can be a problem. To overcome these side effects, small peptides are considered therapeutic agents. We previously identified the small wound healing peptide AES16-2M with a sequence of REGRT, and examined its effects on AD in this study. Interestingly, the administration of AES16-2M downregulated the AD disease score, ear thickness, serum IgE, and thymic stromal lymphopoietin (TSLP) in AD mice. The thickness of the epidermal layer was also improved by AES16-2M treatment. In addition, quantities of IL-4-, IL-13-, and IL-17-producing CD4 T cells from peripheral lymph nodes and spleens were reduced by injection of AES16-2M. Furthermore, the expression of TSLP was significantly reduced in AES16-2M-treated human keratinocytes. Therefore, these results suggest that AES16-2M can be a novel candidate for AD treatment.

Lysyl-Transfer RNA Synthetase Induces the Maturation of Dendritic Cells through MAPK and NF-κB Pathways, Strongly Contributing to Enhanced Th1 Cell Responses.

In addition to essential roles in protein synthesis, lysyl-tRNA synthetase (KRS) is secreted to trigger a proinflammatory function that induces macrophage activation and TNF-α secretion. KRS has been associated with autoimmune diseases such as polymyositis and dermatomyositis. In this study, we investigated the immunomodulatory effects of KRS on bone marrow-derived dendritic cells (DCs) of C57BL/6 mice and subsequent polarization of Th cells and analyzed the underlying mechanisms. KRS-treated DCs increased the expression of cell surface molecules and proinflammatory cytokines associated with DC maturation and activation. Especially, KRS treatment significantly increased production of IL-12, a Th1-polarizing cytokine, in DCs. KRS triggered the nuclear translocation of the NF-κB p65 subunit along with the degradation of IκB proteins and the phosphorylation of MAPKs in DCs. Additionally, JNK, p38, and ERK inhibitors markedly recovered the degradation of IκB proteins, suggesting the involvement of MAPKs as the upstream regulators of NF-κB in the KRS-induced DC maturation and activation. Importantly, KRS-treated DCs strongly increased the differentiation of Th1 cells when cocultured with CD4+ T cells. The addition of anti-IL-12-neutralizing Ab abolished the secretion of IFN-γ in the coculture, indicating that KRS induces Th1 cell response via DC-derived IL-12. Moreover, KRS enhanced the OVA-specific Th1 cell polarization in vivo following the adoptive transfer of OVA-pulsed DCs. Taken together, these results indicated that KRS effectively induced the maturation and activation of DCs through MAPKs/NF-κB-signaling pathways and favored DC-mediated Th1 cell response.

The Role of Erythroid Differentiation Regulator 1 (ERDR1) in the Control of Proliferation and Photodynamic Therapy (PDT) Response.

Erythroid differentiation regulator 1 (ERDR1) was newly identified as a secreted protein that plays an essential role in maintaining cell growth homeostasis. ERDR1 enhances apoptosis at high cell densities, leading to the inhibition of cell survival. Exogenous ERDR1 treatment decreases cancer cell proliferation and tumor growth as a result of increased apoptosis via the regulation of apoptosis-related gene expression. Moreover, ERDR1 plays a pivotal role in skin diseases; ERDR1 expression in actinic keratosis (AK) is negatively correlated with the increase in apoptosis. Because of its high specificity and efficiency, photodynamic therapy (PDT) is a common therapy for patients with various skin diseases, including cancer. Many studies indicate that apoptosis is mainly induced by PDT treatment. As an apoptosis inducer, the recovery of the ERDR1 expression after PDT is correlated with good therapeutic outcomes. Here, we review recent findings that highlight the function of ERDR1 in the control of apoptosis. Thus, ERDR1 may have a role in the apoptosis regulation of target cells in the lesions, as the recovery of its expression after PDT is correlated with good therapeutic outcomes.

Erythroid Differentiation Regulator 1 Ameliorates Collagen-Induced Arthritis via Activation of Regulatory T Cells.

Erythroid differentiation regulator 1 (Erdr1) has been identified as an anti-inflammatory factor in several disease models, including collagen-induced arthritis (CIA), but its exact mechanisms are still not fully understood. Here, the involvement of regulatory T (Treg) cells in Erdr1-improved CIA was investigated. In the CIA model, Erdr1 was confirmed to reduce collagen-specific IgM in plasma and plasma cells in draining lymph nodes. Importantly, the downregulated Treg cell ratio in draining lymph nodes from CIA mice was recovered by Erdr1 treatment. In addition, administration of Erdr1 improved the CIA score and joint tissue damage, while it revealed no effect in Treg cell-depleted CIA mice, indicating that Treg cells mediate the therapeutic effects of Erdr1 in the CIA model. Results from in vitro experiments also demonstrated that Erdr1 significantly induced Treg cell differentiation and the expression of Treg activation markers, including CD25, CD69, and CTLA4 in CD4+Foxp3+ cells. Furthermore, Erdr1-activated Treg cells dramatically suppressed the proliferation of responder T cells, suggesting that they are functionally active. Taken together, these results show that Erdr1 induces activation of Treg cells and ameliorates rheumatoid arthritis via Treg cells.

The Novel Synthetic Peptide AESIS-1 Exerts a Preventive Effect on Collagen-Induced Arthritis Mouse Model via STAT3 Suppression.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that is associated with systemic inflammation and results in the destruction of joints and cartilage. The pathogenesis of RA involves a complex inflammatory process resulting from the action of various proinflammatory cytokines and, therefore, many novel therapeutic agents to block cytokines or cytokine-mediated signaling have been developed. Here, we tested the preventive effects of a small peptide, AESIS-1, in a mouse model of collagen-induced arthritis (CIA) with the aim of identifying a novel safe and effective biological for treating RA. This novel peptide significantly suppressed the induction and development of CIA, resulting in the suppression of synovial inflammation and cartilage degradation in vivo. Moreover, AESIS-1 regulated JAK/STAT3-mediated gene expression in vitro. In particular, the gene with the most significant change in expression was suppressor of cytokine signaling 3 (Socs3), which was enhanced 8-fold. Expression of the STAT3-specific inhibitor, Socs3, was obviously enhanced dose-dependently by AESIS-1 at both the mRNA and protein levels, resulting in a significant reduction of STAT3 phosphorylation in splenocytes from severe CIA mice. This indicated that AESIS-1 regulated STAT3 activity by upregulation of SOCS3 expression. Furthermore, IL-17 expression and the frequency of Th17 cells were considerably decreased by AESIS-1 in vivo and in vitro. Collectively, our data suggest that the novel synthetic peptide AESIS-1 could be an effective therapeutic for treating RA via the downregulation of STAT3 signaling.

AIMP1 regulates TCR signaling and induces differentiation of regulatory T cells by interfering with lipid raft association.

In addition to a role in translation, AIMP1 is secreted to affect various immune cells, such as macrophages, dendritic cells, B cells, and natural killer cells. However, the direct effects of AIMP1 on T cells have not yet been reported. In this study, we investigated whether AIMP1 could modulate T cell responses directly. Results revealed that AIMP1 significantly inhibited T cell receptor (TCR)-dependent activation and proliferation of CD4 T cells, as well as decreased TCR stimuli-induced Ca2+ influx in CD4 T cells. In addition, microscopic analysis revealed that lipid raft association in response to TCR engagement was significantly reduced in the presence of AIMP1, and the phosphorylation of PLCγ and PI3K was also down-regulated in CD4 T cells by AIMP1. Furthermore, AIMP1 specifically enhanced the differentiation of regulatory T (Treg) cells, while it had no effect on T helper type 1 (Th1), type 2 (Th2), and type 17 (Th17) cell differentiation. Collectively, these results indicate that AIMP1 affects T cells directly by down-regulating TCR signaling complex formation and inducing Treg cell differentiation in CD4 T cells.

Erythroid differentiation regulator 1 strengthens TCR signaling in thymocytes by modulating calcium flux.

Erythroid differentiation regulator 1 (Erdr1) has been identified as a stromal survival factor released under stressful conditions. Previously, Erdr1 was reported to be expressed highly in thymus, but roles of Erdr1 in thymus were not known. Here, the effects of Erdr1 on T cell development were investigated. The expression of Erdr1 was higher in thymus than bone marrow and Erdr1 was detected in both the cortex and medulla of thymus. Erdr1 treatment significantly induced the expression of activation marker, CD69, from thymocytes in the presence of TCR stimuli in vitro and the induction was dependent on increased Ca2+ influx. In addition, in vivo administration of Erdr1 resulted in significant increase of total and positive selected thymocyte numbers, particularly in the number of CD3TCRhiCD69+ DP thymocytes. Taken together, our results show that Erdr1 enhances the strength of TCR signaling and cellularity of thymocytes by amplifying Ca2+ influx in thymocytes receiving TCR signals.

Aminoacyl tRNA Synthetase--Interacting Multifunctional Protein 1 Activates NK Cells via Macrophages In Vitro and In Vivo.

Aminoacyl tRNA synthetase-interacting multifunctional protein 1 (AIMP1) has been reported to have antitumor effects in various tumor models. However, mechanisms by which AIMP1 ameliorates tumorigenesis are not well understood. As NK cells are a major cell type involved in antitumor activities and AIMP1 is known to activate professional APCs, we determined whether AIMP1 induced NK cell activation directly or via these APCs. AIMP1 induced the expression of surface activation markers on murine NK cells in total splenocytes, although AIMP1 did not directly induce these activation markers of NK cells. The inductive effect of AIMP1 on NK cell activation disappeared in macrophage-depleted splenocytes, indicating that macrophages were required for the AIMP1-induced activation of NK cells. Furthermore, coculture experiments showed that AIMP1 activated NK cells in the presence of isolated macrophages, but failed to activate NK cells when cultured alone or with dendritic cells or B cells. Although AIMP1 significantly promoted TNF-α production by macrophages, the secreted TNF-α partially affected the NK cell activation. Transwell cocultivation analysis revealed that direct contact between macrophages and NK cells was required for the AIMP1-induced NK cell activation. In addition, AIMP1 significantly enhanced cytotoxicity of NK cells against Yac-1 cells. Furthermore, the in vivo administration of AIMP1 also induced NK cell activation systemically with a macrophage-dependent manner. Importantly, AIMP1 dramatically reduced the lung metastasis of melanoma cells, which was mediated by NK cells. Taken together, our results show that AIMP1 induces antitumor responses by NK cell activation mainly via macrophages.

Visfatin Promotes Wound Healing through the Activation of ERK1/2 and JNK1/2 Pathway.

Visfatin, a member of the adipokine family, plays an important role in many metabolic and stress responses. The mechanisms underlying the direct therapeutic effects of visfatin on wound healing have not been reported yet. In this study, we examined the effects of visfatin on wound healing in vitro and in vivo. Visfatin enhanced the proliferation and migration of human dermal fibroblasts (HDFs) and keratinocytes the expression of wound healing-related vascular endothelial growth factor (VEGF) in vitro and in vivo. Treatment of HDFs with visfatin induced activation of both extracellular signal-regulated kinases 1 and 2 (ERK1/2) and c-Jun N-terminal kinases 1 and 2 (JNK1/2) in a time-dependent manner. Inhibition of ERK1/2 and JNK1/2 led to a significant decrease in visfatin-induced proliferation and migration of HDFs. Importantly, blocking VEGF with its neutralizing antibodies suppressed the visfatin-induced proliferation and migration of HDFs and human keratinocytes, indicating that visfatin induces the proliferation and migration of HDFs and human keratinocytes via increased VEGF expression. Moreover, visfatin effectively improved wound repair in vivo, which was comparable to the wound healing activity of epidermal growth factor (EGF). Taken together, we demonstrate that visfatin promotes the proliferation and migration of HDFs and human keratinocytes by inducing VEGF expression and can be used as a potential novel therapeutic agent for wound healing.

Hydrophilic Astragalin Galactoside Induces T Helper Type 1-Mediated Immune Responses via Dendritic Cells.

A flavonoid Astragalin (kaempferol-3-O-ß-d-glucopyranoside, Ast) has several biological activities including anti-oxidant, anti-HIV, and anti-allergic effects. Nonetheless, its insolubility in hydrophilic solvents imposes restrictions on its therapeutic applications. In this study, we investigated the effects of water-soluble astragalin-galactoside (kaempferol-3-O-ß-d-isomaltotrioside, Ast-Gal) on murine bone marrow-derived dendritic cell (DC) maturation and T helper (Th) cell-mediated immune responses. Ast-Gal significantly increased maturation and activation of DCs through the upregulation of surface markers, such as cluster of differentiation (CD)80, CD86, and Major histocompatibility complex (MHC) II in a dose-dependent manner, while Ast had little effects. Additionally, Ast-Gal-treated DCs markedly secreted immune-stimulating cytokines such as interleukin (IL)-1ß, IL-6, and IL-12. Importantly, Ast-Gal strongly increased expression of IL-12, a polarizing cytokine of Th1 cells. In a co-culture system of DCs and CD4⁺ T cells, Ast-Gal-treated DCs preferentially differentiates naïve CD4⁺ T cells into Th1 cells. The addition of neutralizing IL-12 monoclonal antibody (mAb) to cultures of Ast-Gal-treated DCs and CD4⁺ T cells significantly decreased interferon (IFN)-γ production, thereby indicating that Ast-Gal-stimulated DCs enhance the Th1 response through IL-12 production by DCs. Injection with Ast-Gal-treated DCs in mice increased IFN-γ-secreting Th1 cell population. Collectively, these findings indicate that hydrophilically modified astragalin can enhance Th1-mediated immune responses via DCs and point to a possible application of water-soluble astragalin-galactoside as an immune adjuvant.

IL-33 inhibits the differentiation and immunosuppressive activity of granulocytic myeloid-derived suppressor cells in tumor-bearing mice.

Myeloid-derived suppressor cells (MDSCs) contribute to tumor-mediated immune escape by suppressing antitumor immune responses. Interleukin-33 (IL-33) is capable of regulating various immune cell populations; however, the effects of IL-33 on the differentiation of MDSCs have not been well characterized. In this study, we evaluated the effects of IL-33 on MDSCs and found that IL-33 significantly reduced the differentiation of lineage-negative bone marrow progenitor cells into granulocytic MDSCs (G-MDSCs). IL-33-treated MDSCs exhibited diminished immunosuppressive capacity; reduced inhibition on T-cell proliferation and interferon-γ production, and diminished production of reactive oxygen species. However, IL-33 treatment did not affect the frequency of monocytic MDSCs (M-MDSCs) or their production of nitric oxide and expression of arginase-1. Additionally, compared with control MDSCs, IL-33-treated MDSCs had reduced capacity to induce the differentiation or expansion of Treg cells. Moreover, in vivo IL-33 administration significantly decreased MDSCs and G-MDSCs accumulation in the spleen and tumor microenvironment. Also, despite increasing CD4+ and CD8+ T-cell infiltration, IL-33 administration markedly decreased Treg-cell population in tumor microenvironment. Taken together, our findings indicate that IL-33 reduces the frequency and immunosuppressive activity of G-MDSCs and ultimately the extent of tumor growth.

IL-33-matured dendritic cells promote Th17 cell responses via IL-1ß and IL-6.

IL-33 is associated with a variety of autoimmune diseases, such as sclerosis, inflammatory bowel disease, and rheumatoid arthritis. Although IL-33 is mainly involved in the induction of Th2 cells, however, the relationship between IL-33 and Th17 cells is still largely unknown. In this study, we investigated the effects of IL-33 on DC-mediated CD4+ T cell activation and Th17 cell differentiation because DCs are essential cells for presenting self-antigens to CD4+ T cells in autoimmune disease conditions. OT-II mice were injected with IL-33-treated DCs or untreated DCs that were primed by OVA323-339 peptide, and their Th17 cell responses were compared. Th17 cell population and IL-17 expression levels were significantly increased in draining lymph nodes of mice injected with IL-33-treated DCs, compared with those in mice injected with untreated DCs. IL-33 treatment maturated DCs to present self-antigens and to increase production of proinflammatory cytokines such as IL-1ß and IL-6, which have a crucial role in Th17 cell differentiation. We found that the IL-33-matured DCs enhanced the expression of an early T cell activation marker (CD69) and the Th17 master transcription factor (RORγt), but IL-33 did not directly affect CD4+ T cell differentiation or increase Th17 polarization. Notably, neutralizing IL-1ß and/or IL-6 significantly decreased IL-17 expression levels and Th17 cell population which were increased by the coculture of CD4+ T cells with IL-33-matured DCs, indicating that IL-33 may induce Th17 cell responses via IL-1ß and IL-6 derived from IL-33-matured DCs.

The Effects of Artemisinin on the Cytolytic Activity of Natural Killer (NK) Cells.

Artemisinin, a chemical compound used for the treatment of malaria, has been known to show anti-cancer activity. However, the effect of this chemical on natural killer (NK) cells, which are involved in tumor killing, remains unknown. Here, we demonstrate that artemisinin exerts a potent anti-cancer effect by activating NK cells. NK-92MI cells pre-treated with artemisinin were subjected to a cytotoxicity assay using K562 cells. The results showed that artemisinin significantly enhances the cytolytic activity of NK cells in a dose-dependent manner. Additionally, the artemisinin-enhanced cytotoxic effect of NK-92MI cells on tumor cells was accompanied by the stimulation of granule exocytosis, as evidenced by the detection of CD107a expression in NK cells. Moreover, this enhancement of cytotoxicity by artemisinin was also observed in human primary NK cells from peripheral blood. Our results suggest that artemisinin enhances human NK cell cytotoxicity and degranulation. This is the first evidence that artemisinin exerts antitumor activity by enhancing NK cytotoxicity. Therefore, these results provide a deeper understanding of the action of artemisinin and will contribute to the development and application of this class of compounds in cancer treatment strategies.

Aminoacyl-tRNA synthetase-interacting multifunctional protein 1 suppresses tumor growth in breast cancer-bearing mice by negatively regulating myeloid-derived suppressor cell functions.

Myeloid-derived suppressor cells (MDSCs) are one of the most important cell types that contribute to negative regulation of immune responses in the tumor microenvironment. Recently, aminoacyl-tRNA synthetase-interacting multifunctional protein 1 (AIMP1), a novel pleiotropic cytokine, was identified as an antitumor protein that inhibits angiogenesis and induces antitumor responses. However, the effect of AIMP1 on MDSCs in the tumor environment remains unclear. In the present study, we demonstrated that AIMP1 significantly inhibited tumor growth in 4T1 breast cancer-bearing mice and reduced MDSCs population of tumor sites and spleens of tumor-bearing mice. AIMP1 reduced expansion of MDSCs from bone marrow-derived cells in the tumor-conditioned media. AIMP1 also negatively regulated suppressive activities of MDSCs by inhibiting IL-6 and NO production, and Arg-1 expression. Furthermore, treatment of breast cancer-bearing mice with AIMP1 decreased the capacity of MDSCs to suppress T cell proliferation and Treg cell induction. Western blot and inhibition experiments showed that downregulation of MDSCs functions by AIMP1 may result from attenuated activation of STATs, Akt, and ERK. These findings indicate that AIMP1 plays an essential role in negative regulation of suppressive functions of MDSCs. Therefore, it has a significant potential as a therapeutic agent for cancer treatment.

IL-18 enhances immunosuppressive responses by promoting differentiation into monocytic myeloid-derived suppressor cells.

Myeloid-derived suppressor cells (MDSCs) are major immunosuppressive cells that lead to T cell defects in cancer. IL-18 is important in inflammatory and immune responses. IL-18 has been reported to have a dual effect on tumor progression, as it not only stimulates host immune responses, but also exerts procancer effects by inducing immune escape and angiogenesis. In the present study, we investigated the effect of IL-18 on MDSCs and found that IL-18 treatment significantly increased the percentage and the absolute number of monocytic MDSCs (M-MDSCs) via differentiation of CD11b(-) bone marrow progenitor cells. IL-18-induced MDSCs showed enhanced suppression of T cell proliferation and IFN-γ production along with a dramatic increase of M-MDSC suppressive function, including NO production and arginase 1 expression. Although IL-18 decreased the number of granulocytic MDSCs (G-MDSCs) in a concentration-dependent manner, we found that the absolute number of G-MDSCs and their reactive oxygen species production remained unchanged. Additionally, we demonstrated that IL-18-induced M-MDSCs have a more potent suppressive effect on T cell responses with lower IFN-γ production than do G-MDSCs, suggesting that the increased suppressive effect observed in our study resulted from M-MDSCs. Furthermore, in vivo administration of IL-18 significantly increased the accumulation of M-MDSCs in the tumor microenvironment. Taken together, our findings indicate that IL-18 specifically enhances the differentiation and function of M-MDSCs, leading to immunosuppression.

Therapeutic Effects of Erythroid Differentiation Regulator 1 on Imiquimod-Induced Psoriasis-Like Skin Inflammation.

Psoriasis is a common skin disease accompanied by chronic inflammation. In previous studies, erythroid differentiation regulator 1 (ERDR1) was shown to have a negative correlation with proinflammatory cytokine IL-18. However, the role of ERDR1 in the inflammatory skin disease psoriasis has not been evaluated. In this study, to investigate the role of ERDR1 in psoriasis, recombinant ERDR1 was injected intraperitoneally into a psoriasis mouse model. Recombinant ERDR1 (rERDR1) significantly alleviated the symptoms of psoriasis-like skin inflammation and reduced the mRNA of various psoriasis-related markers, including keratin 14, S100A8, and Th17-related cytokines IL-17 and IL-22, suggesting that rERDR1 exerts therapeutic effects on psoriasis via the regulation of Th17 functions. Additionally, the expression of CCL20, a well-known Th17 attracting chemokine, was determined. CCL20 expression significantly decreased in the rERDR1-injected group compared with the vehicle (PBS)-injected group. CCR6 expression in the psoriatic lesional skin was also decreased by rERDR1 administration, implying the inhibition of CCR6-expressing Th17 cell chemotaxis via the downregulation of CCL20. Taken together, this study provides the first evidence that ERDR1 may be a potential therapeutic target for psoriasis.

Erdr1 Suppresses Murine Melanoma Growth via Regulation of Apoptosis.

Melanoma, one of the aggressive cancers, is known to be resistant to chemotherapy. Because of its aggressive nature, effectively inducing apoptosis is necessary to treat melanoma. Erythroid differentiation regulator 1 (Erdr1) is known to be a stress-related survival factor exhibiting anti-cancer effects in several cancers. However, little is known about the functions and underlying mechanisms of Erdr1 so far. To demonstrate the effect of Erdr1 in melanoma apoptosis, recombinant murine Erdr1 was injected into mice implanted with B16F10 melanoma cells. In vivo tumor growth was significantly inhibited in mice injected with Erdr1 compared to the control. In addition, the tumor from Erdr1-injected mice showed an increased level of apoptosis. Accordingly, apoptosis-regulating factors including anti-apoptotic marker Bcl-2 and pro-apoptotic marker Bax in the tumor tissues were examined. As expected, the decreased level of Bcl-2 and increased level of Bax were detected in tumors within the mice injected with Erdr1. Based on the in vivo study, the role of Erdr1 in tumor apoptosis was further tested by incubating it with cells of the murine melanoma cell line B16F10. Erdr1-induced apoptosis in B16F10 cells was observed. Additionally, Erdr1 downregulated STAT3 activity, inhibiting apoptosis via regulation of the Bcl-2 family. Overall, data demonstrate that Erdr1 induced murine melanoma apoptosis through the regulation of Bcl-2 and Bax. These findings suggest that Erdr1 is a novel regulator of apoptosis in melanoma.