Alteration in genes which takes place during malignant conversion and progression could be potential targets for gene therapy. We previously identified REIC/Dkk-3 as a gene whose expression is reduced in many human cancers. Here, we showed that expression of REIC/Dkk-3 was consistently reduced in human prostate cancer tissues in a stagedependent manner. Forced expression of REIC/Dkk-3 induced apoptosis in human prostate cancer cell lines lacking endogenous REIC/Dkk-3 expression but not in REIC/Dkk-3-proficient normal prostate epithelial and stromal cells. The apoptosis involved c-Jun-NH 2 -kinase activation, mitochondrial translocation of Bax, and reduction of Bcl-2. A single injection of an adenovirus vector carrying REIC/Dkk-3 showed a dramatic antitumor effect on a xenotransplanted human prostate cancer. Thus, REIC/Dkk-3 could be a novel target for gene-based therapy of prostate cancer. (Cancer Res 2005; 65(21): 9617-22)
Objective. To examine whether topical treatment of wild-type mice with Toll-like receptor 7 (TLR-7) agonists leads to lupus-like autoimmunity.Methods. Wild-type FVB/N, BALB/c, and C57BL/6 mice were treated with the topical TLR-7 agonist imiquimod or R848 administered to the ear 3 times weekly. During treatment, the mice were monitored for serum autoantibody and creatinine levels as well as histopathology of the kidneys, spleens, livers, hearts, and skin. Immunologic abnormalities were analyzed by immunohistochemistry, quantitative reverse transcription-polymerase chain reaction, and fluorescence-activated cell sorting. The role of plasmacytoid dendritic cells (PDCs) in the development of autoimmune disease was validated by in vivo treatment with an anti-PDC antibody. Diseased mice underwent ultraviolet B irradiation, to evaluate skin photosensitivity. The disease-causing effect of topical application of imiquimod was compared with that of systemic (intraperitoneal) administration. TLR-7-and TLR-9-deficient mice were used to validate the role of TLR-7.Results. Wild-type mice of different genetic backgrounds developed systemic autoimmune disease following 4 weeks of topical treatment with imiquimod or R848, with elevated levels of autoantibodies to doublestranded DNA and multiple organ involvement, including glomerulonephritis, hepatitis, carditis, and photosensitivity. Expression of Ifna and Mx1, the interferon-␣-stimulated gene, was up-regulated in the organs of imiquimod-treated mice. However, disease caused by intraperitoneal injection of imiquimod was less severe than that induced by topical application. In vivo depletion of PDCs by a specific antibody protected mice against the autoimmunity induced by topical administration of imiquimod, suggesting a role of PDCs. Furthermore, TLR-7-deficient mice, but not TLR-9-deficient mice, were protected against autoimmunity.Conclusion. This protocol provides a novel model of inducible systemic lupus erythematosus in wild-type mice and underscores the skin as the primary organ that allows TLR-7 agonists to induce SLE.
Epidermal keratinocytes in psoriatic lesions are characterized by activated Stat3, and increased levels of cytokines and growth factors that promote Stat3 activation have been found within psoriatic lesions. K5.Stat3C transgenic mice, in which keratinocytes express a constitutively active Stat3, develop psoriasis-like skin lesions. In this study, we examined whether STA-21, a small Stat3 inhibitor, could be useful in ameliorating the skin lesions not only in the model mouse but also in human psoriasis. Treatment with STA-21 markedly inhibited the cytokine-dependent nuclear translocation of Stat3 in normal human keratinocytes in vitro. Keratinocyte proliferation was inhibited by STA-21 in a dose-dependent manner through downregulation of c-Myc and cyclin D1, whereas involucrin, transglutaminase 1, and keratin 10 levels were upregulated. Topical application of STA-21 abolished the generation of skin lesions in K5.Stat3C mice. Finally, we treated psoriasis patients with STA-21-containing ointment in a nonrandomized study. Psoriatic lesions in six of the eight patients showed improvement after topical STA-21 treatment for 2 weeks. Therefore, we conclude that targeting Stat3 may lead to a therapy for psoriasis.
Psoriasis is an inflammatory disease with dynamic interactions between the immune system and the skin. The IL-23/Th17 axis plays an important role in the pathogenesis of psoriasis, although the exact contributions of IL-23 and IL-17 in vivo remain unclear. K5.Stat3C transgenic mice constitutively express activated Stat3 within keratinocytes, and these animals develop skin lesions with histological and cytokine profiles similar to those of human plaque psoriasis. In this study, we characterized the effects of anti-mouse IL-17A, anti-mouse IL-12/23p40, and anti-mouse IL-23p19 Abs on the development of psoriasis-like lesions in K5.Stat3C transgenic mice. Treatment with anti–IL-12/23p40 or anti–IL-23p19 Abs greatly inhibited 12-O-tetradecanoylphorbol-13-acetate–induced epidermal hyperplasia in the ears of K5.Stat3C mice, whereas the inhibitory effect of an anti–IL-17A Ab was relatively less prominent. Treatment with anti–IL-12/23p40 or anti–IL-23p19 Abs markedly lowered transcript levels of Th17 cytokines (e.g., IL-17 and IL-22), β-defensins, and S100A family members in skin lesions. However, anti–IL-17A Ab treatment did not affect mRNA levels of Th17 cytokines. Crossing IL-17A–deficient mice with K5.Stat3C mice resulted in partial attenuation of 12-O-tetradecanoylphorbol-13-acetate–induced lesions, which were further attenuated by anti–IL-12/23p40 Ab treatment. FACS analysis of skin-draining lymph node cells from mice that were intradermally injected with IL-23 revealed an increase in both IL-22–producing T cells and NK-22 cells. Taken together, this system provides a useful mouse model for psoriasis and demonstrates distinct roles for IL-23 and IL-17.
An increase in extracellular Ca2+ induces growth arrest and differentiation of human keratinocytes in culture. We examined possible involvement of S100C/A11 in this growth regulation. On exposure of the cells to high Ca2+, S100C/A11 was specifically phosphorylated at 10Thr and 94Ser. Phosphorylation facilitated the binding of S100C/A11 to nucleolin, resulting in nuclear translocation of S100C/A11. In nuclei, S100C/A11 liberated Sp1/3 from nucleolin. The resulting free Sp1/3 transcriptionally activated p21CIP1/WAF1, a representative negative regulator of cell growth. Introduction of anti-S100C/A11 antibody into the cells largely abolished the growth inhibition induced by Ca2+ and the induction of p21CIP1/WAF1. In the human epidermis, S100C/A11 was detected in nuclei of differentiating cells in the suprabasal layers, but not in nuclei of proliferating cells in the basal layer. These results indicate that S100C/A11 is a key mediator of the Ca2+-induced growth inhibition of human keratinocytes in culture, and that it may be possibly involved in the growth regulation in vivo as well.
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