Signal Transducer and Activator of Transcription 3 Is a Key Regulator of Keratinocyte Survival and Proliferation following UV Irradiation

Sano, Shigetoshi; Chan, Keith S.; Kira, Masahiro; Kataoka, Ken; Takagi, Satoshi; Tarutani, Masahito; Itami, Satoshi; Kiguchi, Kaoru; Yokoi, Masayuki; Sugasawa, Kaoru; Mori, Toshio; Hanaoka, Fumio; Takeda, Junji; DiGiovanni, John

doi:10.1158/0008-5472.can-04-4359

Cited by 91 publications

(112 citation statements)

References 51 publications

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“…K5.Stat3C mice were generated as previously reported (17). Briefly, Stat3C cDNA (a gift from Dr. J. Bromberg, Memorial Sloan Kettering Cancer Center, New York, NY) was ligated into the pBK5 construct, followed by digestion with EcoRI.…”

Section: Patients and Skin Samplesmentioning

confidence: 99%

Cathepsin K Is Involved in Development of Psoriasis-like Skin Lesions through TLR-Dependent Th17 Activation

Hirai

Kanda

Satô

et al. 2013

The Journal of Immunology

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Cathepsins (CTSs) are lysosomal cysteine proteases that play an important role in the turnover of intracellular proteins and extracellular proteins, such as the degradation of extracellular matrices and the processing of antigenic proteins. A CTS inhibitor, NC-2300, not only suppresses bone erosion by inhibition of cathepsin K (CTSK), but also ameliorates paw swelling at inflamed joints in adjuvant-induced arthritis in rats. It has been demonstrated that the amelioration of joint inflammation by NC-2300 is mediated by the downregulation of cytokine expression in dendritic cells, which are essential for Th17 activation. In this work, we studied the role for CTSs in the pathogenesis of psoriasis-like lesion in K5.Stat3C mice, a mouse model of psoriasis, in which Th17 contributes to lesion development similar to psoriasis. Psoriatic lesions expressed increased levels of Ctsk and Ctss mRNA compared with uninvolved skin and normal control skin. Similarly, the epidermis and dermis in K5.Stat3C mice demonstrated increased CTSK activities, which were sensitive to NC-2300. Topical treatment with NC-2300 significantly ameliorated 12-O-tetradecanoylphorbol-13-acetate–induced psoriasis-like lesions in K5.Stat3C mice, and downregulated the expression of IL-12, IL-23, and Th17 cytokines. In vitro experiments revealed that TLR7 activation of bone marrow–derived myeloid dendritic cells led to increase in IL-23 at mRNA and protein levels, which were downregulated by NC-2300. These results suggest that CTSK plays a role in development of psoriatic lesions through TLR7-dependent Th17 polarization.

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Section: Patients and Skin Samplesmentioning

confidence: 99%

Cathepsin K Is Involved in Development of Psoriasis-like Skin Lesions through TLR-Dependent Th17 Activation

Hirai

Kanda

Satô

et al. 2013

The Journal of Immunology

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“…1,2,6 Histologically, skin inflammation caused by UVB is characterized by dilation of blood vessels, 1,2 infiltration of neutrophils, 1,7-10 and epidermal thickening. 2,9,[11][12][13] Biochemical changes including cytokine expression are also induced during UVB-induced acute skin inflammation. 1 UVBinduced skin inflammatory reactions constitute a potent tumor-promoting event that contributes to photocarcinogenesis.…”

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confidence: 99%

Phospholipase Cɛ has a crucial role in ultraviolet B-induced neutrophil-associated skin inflammation by regulating the expression of CXCL1/KC

Oka

Edamatsu

Kunisada

et al. 2011

Laboratory Investigation

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Phospholipase C (PLC) e is a phosphoinositide-specific PLC regulated by small GTPases including Ras and Rap. We previously demonstrated that PLCe has an important role in the development of phorbol ester-induced skin inflammation. In this study, we investigated the role of PLCe in ultraviolet (UV) B-induced acute inflammatory reactions in the skin. Wild-type (PLCe þ / þ ) and PLCe gene knockout (PLCe À/À ) mice were irradiated with a single dose of UVB at 1, 2.5, and 10 kJ/m 2 on the dorsal area of the skin, and inflammatory reactions in the skin were histologically evaluated up to 168 h after irradiation. In PLCe þ / þ mice, irradiation with 1 and 2.5 kJ/m 2 UVB resulted in dose-dependent neutrophil infiltration in the epidermis at 24 and 48 h after irradiation. When mice were irradiated with 10 kJ/m 2 of UVB, most mice developed skin ulcers by 48 h and these ulcers became more severe at 168 h. In PLCe À/À mice, UVB (1 or 2.5 kJ/m 2 )-induced neutrophil infiltration was markedly suppressed compared with PLCe þ / þ mice. The suppression of neutrophil infiltration in PLCe À/À mice was accompanied by attenuation of UVB-induced production of CXCL1/keratinocyte-derived chemokine (KC), a potent chemokine for neutrophils, in the whole skin. Cultured epidermal keratinocytes and dermal fibroblasts produced CXCL1/KC in a PLCe-dependent manner after UVB irradiation, and the UVB-induced upregulation of CXCL1/KC in these cells was significantly abolished by a PLC inhibitor. Furthermore, UVB-induced epidermal thickening was noticeably reduced in the skin of PLCe À/À mice. These results indicate that PLCe has a crucial role in UVB-induced acute inflammatory reactions such as neutrophil infiltration and epidermal thickening by at least in part regulating the expression of CXCL1/KC in skin cells such as keratinocytes and fibroblasts.

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“…Because UVR initiates signal transduction and activates transcription factors that result in changes of gene expression of cytokines and their receptors (26), the immunosuppressive effects of cis-UCA may be induced by its ability to initiate gene transcription. Despite considerable research into the effects of UVR on the activation of transcription factors and gene expression (27)(28)(29)(30)(31)(32), a comprehensive analysis of the effects of cis-UCA on those events has not been conducted.…”

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confidence: 99%

cis-Urocanic Acid Initiates Gene Transcription in Primary Human Keratinocytes

Kaneko

Smetana-Just

Matsui³

et al. 2008

The Journal of Immunology

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It is well established that solar UV radiation (UVR) suppresses cutaneous cell-mediated immunity in humans. trans-Urocanic acid (trans-UCA) is a major UVR-absorbing skin molecule that undergoes a photoisomerization to its cis-isomer following UVR exposure. Animal studies have demonstrated that cis-UCA plays a role in UVR-induced immune suppression, but the molecular mechanisms of action of cis-UCA are not fully understood. In this study, we examined changes in gene expression and synthesis of cytokines and PGE2 following UCA treatment of primary human keratinocytes. A limited microarray analysis of keratinocytes from two donors indicated that ∼400 genes were induced by solar-simulated radiation (SSR), 16 of which were also up-regulated by cis-UCA. In contrast, trans-UCA had little or no effect on gene expression. The genes up-regulated by both cis-UCA and SSR were associated with apoptosis, cell growth arrest, cytokines, and oxidative stress. Further studies using primary keratinocytes from four new donors showed that PG-endoperoxide synthase-2 was dramatically induced by cis-UCA, resulting in an enhanced secretion of PGE2 into the cell culture supernatant. cis-UCA also increased cytokine protein production such as that of TNF-α, IL-6, and IL-8 in a dose-dependent manner. SSR had the same effect as cis-UCA, but trans-UCA had no effect. In addition, activation of NF-κB and lipid peroxidation were induced by cis-UCA and SSR, but not trans-UCA, suggesting possible upstream events of the gene expression changes. The data suggest that the induction of immune suppression by cis-UCA may involve the initiation of gene transcription of immunomodulatory mediators in primary human keratinocytes.

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Signal Transducer and Activator of Transcription 3 Is a Key Regulator of Keratinocyte Survival and Proliferation following UV Irradiation

Cited by 91 publications

References 51 publications

Cathepsin K Is Involved in Development of Psoriasis-like Skin Lesions through TLR-Dependent Th17 Activation

Cathepsin K Is Involved in Development of Psoriasis-like Skin Lesions through TLR-Dependent Th17 Activation

Phospholipase Cɛ has a crucial role in ultraviolet B-induced neutrophil-associated skin inflammation by regulating the expression of CXCL1/KC

cis-Urocanic Acid Initiates Gene Transcription in Primary Human Keratinocytes

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