8-Methoxypsoralen Plus Ultraviolet A Therapy Acts via Inhibition of the IL-23/Th17 Axis and Induction of Foxp3+ Regulatory T Cells Involving CTLA4 Signaling in a Psoriasis-Like Skin Disorder

Singh, Tejbir; Schön, Michael P.; Wallbrecht, Katrin; Michaelis, Kai; Rinner, Beate; Mayer, Gerlinde; Schmidbauer, Ulrike; Strohmaier, Heimo; Wang, Xiaojing; Wolf, Peter

doi:10.4049/jimmunol.0903719

Cited by 112 publications

(110 citation statements)

References 56 publications

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“…Studies have shown that although TGF␤1 has an anti-inflammatory effect in internal organs as evidenced by autoimmune responses in TGF␤1 knockout mice, 35,36 keratinocyte-specific TGF␤1 overexpression causes Th1/Th17-associated skin inflammation. [37][38][39] Consistently, keratinocyte-specific Smad7 overexpression blocked T-cell infiltration more significantly than macrophage infiltration ( Figure 5), which could enable the remaining macrophages to promote wound repair. 27,28 Additionally, although Smad7 transgene is not expressed in the stroma, reduced pSmad2 staining was observed in the stroma of Smad7 tg wounds.…”

Section: Stromal Effects Of Epithelial-specific Smad7 Overexpression mentioning

confidence: 59%

Temporal Smad7 Transgene Induction in Mouse Epidermis Accelerates Skin Wound Healing

Han

Dijke

et al. 2011

The American Journal of Pathology

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The expression of Smad7, a tumor growth factor-␤ (TGF␤) antagonist, is increased during cutaneous wound healing. To assess this significance, we temporally induced Smad7 transgene expression in wounded skin in gene-switch-Smad7 transgenic (Smad7 tg) mice. Smad7 induction in epidermal keratinocytes caused an increase in keratinocyte proliferation with reduced Smad2 activation, indicating that Smad7 abrogated TGF␤-mediated growth inhibition. Additionally, wounded skin from Smad7 tg mice exhibited accelerated re-epithelialization, with increased activation of extracellular signal-regulated kinase (Erk), and an in vitro migration assay revealed that Erk activation contributed to Smad7-mediated keratinocyte migration. Notably, epidermis-specific Smad7 transgene expression also has a profound effect on the wound stroma, resulting in reduced inflammation, angiogenesis, and production of type I collagen. Reduced Smad2 activation was observed in wounded stroma from Smad7 transgenic (Smad7 tg) mice, possibly owing to fewer infiltrated TGF␤-producing leukocytes compared to those in wounds from control mice. Because Smad7 is not secreted, these effects could reflect functional changes in Smad7 tg keratinocytes. Supporting this notion, the activation of NF-B, a nonsecreted protein complex that transcriptionally activates inflammatory cytokines, was reduced in wounded epidermis from Smad7 tg mice compared to that in wounded wildtype epidermis. In sum, epidermal Smad7 overexpression accelerated wound healing through its direct effects on keratinocyte proliferation and migration, and through indirect effects on wound stroma.

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Section: Stromal Effects Of Epithelial-specific Smad7 Overexpression mentioning

confidence: 59%

Temporal Smad7 Transgene Induction in Mouse Epidermis Accelerates Skin Wound Healing

Han

Dijke

et al. 2011

The American Journal of Pathology

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“…This treatment is used against psoriasis and various other dermatoses and results in premature skin aging in vivo and in cellular senescence in vitro (reviewed in Wlaschek et al, 2003). Therefore, we exposed C57BL/6mice to PUVA doses reported to induce cellular senescence in vivo (Singh et al, 2010). Forty-eight hours after treatment, we observed a significant induction of miR-21 using at least 5 animals per group (Fig.…”

Section: Cdc25a and Nfib Knock-down Phenocopies The Effect Of Mir-21 mentioning

confidence: 87%

High levels of onco-miR-21 contribute to the senescence-induced growth arrest in normal human cells and its knock-down increases the replicative lifespan

Dellago

Preschitz-Kammerhofer

Terlecki‐Ζaniewicz

et al. 2015

Experimental Gerontology

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SummaryCellular senescence of normal human cells has by now far exceeded its initial role as a model system for aging research. Many reports show the accumulation of senescent cells in vivo, their effect on their microenvironment and its double-edged role as tumour suppressor and promoter. Importantly, removal of senescent cells delays the onset of age-associated diseases in mouse model systems. To characterize the role of miRNAs in cellular senescence of endothelial cells, we performed miRNA arrays from HUVECs of five different donors. Twelve miRNAs, comprising hsa-miR-23a, hsa-miR-23b, hsa-miR-24, hsa-miR-27a, hsa-miR-29a, hsa-miR-31, hsa-miR-100, hsa-miR-193a, hsa-miR-221, hsa-miR-222 and hsa-let-7i are consistently up-regulated in replicatively senescent cells. Surprisingly, also miR-21 was found up-regulated by replicative and stress-induced senescence, despite being described as oncogenic. Transfection of early passage endothelial cells with miR-21 resulted in lower angiogenesis, and less cell proliferation mirrored by up-regulation of p21 CIP1 and down-regulation of CDK2. These two cell-cycle regulators are indirectly regulated by miR-21 via its validated direct targets NFIB (Nuclear factor 1 B-type), a transcriptional inhibitor of p21 CIP1, and CDC25A, which regulates CDK2 activity by dephosphorylation. Knock-down of either NFIB or CDC25A shows a phenocopy of over-expressing miR-21 in regard to cellcycle arrest. Finally, miR-21 over-epxression reduces the replicative lifespan, while stable knock-down by sponges extends the replicative lifespan of endothelial cells. Therefore, we propose that miR-21 is the first miRNA that upon its knock-down extends the replicative lifespan of normal human cells.

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“…property of UV is a key event in skin carcinogenesis 1 ; but it may also have beneficial effects, including protection from multiple sclerosis, 2 enhancing allograft tolerance, 3 as well as treating psoriasis, 4 atopic dermatitis, 5 and graft-versus-host disease. 6 Other health benefits of UV exposure include vitamin D synthesis 7 and the production of antimicrobial peptides.…”

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confidence: 99%

The Immune-Modulating Cytokine and Endogenous Alarmin Interleukin-33 Is Upregulated in Skin Exposed to Inflammatory UVB Radiation

Byrne

Beaugie

O’Sullivan

et al. 2011

The American Journal of Pathology

105

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The cellular and molecular mechanisms by which UV radiation modulates inflammation and immunity while simultaneously maintaining skin homeostasis is complex and not completely understood. Similar to the effects of UV, IL-33 has potent immune-modulating properties that are mediated by the downstream induction of cytokines and chemokines. We have discovered that exposure of mice in vivo or human skin samples ex vivo to inflammatory doses of UVB induced IL-33 expression within the epidermal and dermal skin layers. Using a combination of murine cell lines and primary human cells, we demonstrate that both UV and the oxidized lipid platelet activating factor induce IL-33 expression in keratinocytes and dermal fibroblasts. Highlighting the significance of these results, we found that administering IL-33 to mice in vivo suppressed the induction of Th1-mediated contact hypersensitivity responses. This may have consequences for skin cancer growth because UV-induced squamous cell carcinomas that evade immunological destruction were found to express significantly higher levels of IL-33. Finally, we demonstrate that dermal mast cells and skininfiltrating neutrophils closely associate with UV-induced IL-33-expressing fibroblasts. Our results therefore identify and support a role for IL-33 as an important early danger signal produced in response to inflammation-inducing UV radiation.

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8-Methoxypsoralen Plus Ultraviolet A Therapy Acts via Inhibition of the IL-23/Th17 Axis and Induction of Foxp3+ Regulatory T Cells Involving CTLA4 Signaling in a Psoriasis-Like Skin Disorder

Cited by 112 publications

References 56 publications

Temporal Smad7 Transgene Induction in Mouse Epidermis Accelerates Skin Wound Healing

Temporal Smad7 Transgene Induction in Mouse Epidermis Accelerates Skin Wound Healing

High levels of onco-miR-21 contribute to the senescence-induced growth arrest in normal human cells and its knock-down increases the replicative lifespan

The Immune-Modulating Cytokine and Endogenous Alarmin Interleukin-33 Is Upregulated in Skin Exposed to Inflammatory UVB Radiation

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