Impaired PI3K/Akt Activation-Mediated NF-κB Inactivation Under Elevated TNF-α Is More Vulnerable to Apoptosis in Vitiliginous Keratinocytes

Kim, Nan-Hyung; Jeon, Songhee; Lee, Hyun-Joo; Lee, Ai-Young

doi:10.1038/sj.jid.5700900

Cited by 60 publications

(55 citation statements)

References 20 publications

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“…This finding is in agreement with a recent report [46] describing significantly higher levels of TNF-alpha and FasL in the depigmented epidermis, which indicates a role for these factors in increasing apoptosis. In this study, PTEN (phosphatase and tension homologue), which could inhibit the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signalling pathway was significantly higher in the depigmented epidermis, implying that vitiliginous keratinocytes may be more susceptible to TNF-alphamediated apoptosis through impaired Akt and NF-kB activation.…”

Section: Discussionsupporting

confidence: 95%

Ultrastructural and functional alterations of mitochondria in perilesional vitiligo skin

Prignano

Pescitelli

Becatti

et al. 2009

Journal of Dermatological Science

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Section: Discussionsupporting

confidence: 95%

Ultrastructural and functional alterations of mitochondria in perilesional vitiligo skin

Prignano

Pescitelli

Becatti

et al. 2009

Journal of Dermatological Science

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“…Therefore, it is logical that the above pathways are commonly involved in IL-31 and IL-33-induced effects on eosinophils cultured with dermal fibroblasts in the present study. Moreover, our findings on signaling mechanism in fibroblasts concurred with some previous studies that showed the involvement of PI3K-Akt, MAPKs and NF-κB pathways in regulating cytokine and chemokine release from keratinocytes [49]–[51].…”

Section: Discussionsupporting

confidence: 91%

Activation of Eosinophils Interacting with Dermal Fibroblasts by Pruritogenic Cytokine IL-31 and Alarmin IL-33: Implications in Atopic Dermatitis

et al. 2012

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BackgroundIL-31 is a pruritogenic cytokine, and IL-33 is an alarmin for damaging inflammation. They together relate to the pathogenesis of atopic dermatitis (AD). Eosinophil infiltration into the inner dermal compartment is a predominant pathological feature of AD. We herein investigated the in vitro inflammatory effects of IL-31 and IL-33 on the activation of human eosinophils and dermal fibroblasts.Methodology/Principal FindingsReceptors, adhesion molecules and signaling molecules were assessed by Western blot or flow cytometry. Chemokines and cytokine were quantitated by multiplex assay. Functional IL-31 receptor component IL-31RA, OSMR-β and IL-33 receptor component ST2 were constitutively expressed on the surface of eosinophils. Co-culture of eosinophils and fibroblasts significantly induced pro-inflammatory cytokine IL-6 and AD-related chemokines CXCL1, CXCL10, CCL2 and CCL5. Such inductions were further enhanced with IL-31 and IL-33 stimulation. IL-31 and IL-33 could significantly provoke the release of CXCL8 from eosinophils and fibroblasts, respectively, which was further enhanced upon co-culture. In co-culture, eosinophils and fibroblasts were the main source for the release of CCL5, and IL-6, CXCL1, CXCL8, CXCL10 and CCL2, respectively. Direct interaction between eosinophils and fibroblasts was required for CXCL1, CXCL10, CXCL8 and CCL5 release. Cell surface expression of intercellular adhesion molecule-1 on eosinophils and fibroblasts was up-regulated in co-culture upon IL-31 and IL-33 stimulation. The interaction between eosinophils and fibroblasts under IL-31 and IL-33 stimulation differentially activated extracellular signal-regulated kinase, c-Jun N-terminal kinase, p38 mitogen-activated protein kinase, nuclear factor-κB and phosphatidylinositol 3-kinase–Akt pathways. Using specific signaling molecule inhibitors, the differential induction of IL-31 and IL-33-mediated release of cytokines and chemokines such as IL-6 and CXCL8 from co-culture should be related to their distinct activation profile of intracellular signaling pathways.Conclusions/SignificanceThe above findings suggest a crucial immunopathological role of IL-31 and IL-33 in AD through the activation of eosinophils-fibroblasts interaction via differential intracellular signaling mechanisms.

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“…However, the mechanism through which cytokines affect pigmentation and dendrites is not fully understood56 and warrants further investigation.…”

Section: Discussionmentioning

confidence: 99%

Novel approaches to vitiligo treatment via modulation of mTOR and NF-κB pathways in human skin melanocytes

Wan

Lin²,

Zhang

et al. 2017

Int. J. Biol. Sci.

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Vitiligo is a skin depigmentation disorder with an increasing prevalence. Among recognized mechanisms is the oxidative stress that affects melanocytes which are responsible for skin pigmentation. Studies have shown that high concentration of hydrogen peroxide, or H2O2, induces apoptotic activities. Few studies have been done with lower doses of H2O2. Using human skin melanocytes, we investigated the effect of moderate concentration of H2O2 on melanocyte dendrites. Confocal data show that H2O2 at 250 µM induces loss of dendrites, as indicated by cytoskeletal proteins. α-melanocyte stimulating hormone or α-MSH pretreatment protects against H2O2-induced loss of dendrites, while α-MSH alone enhances dendrites. PI3K/AKT inhibitor LY294002 and mTORC1 inhibitor Rapamycin inhibit α-MSH-induced dendrites. In this study, we also investigated the effect of TNFα on cultured human skin melanocytes, since TNFα plays important roles in vitiligo. Confocal data demonstrate that TNFα induces NFκB activation. Western blot analysis shows that TNFα induces IκB phosphorylation and degradation. Interestingly, α-MSH does not have any effect of TNFα-induced IκB degradation and NF-κB activation. α-MSH, however, activates mTORC1 pathway. TNFα induces p38 but not AMPKα activation. Collectively, our data suggest that modulation of mTOR and NF-κB pathways may be a novel approach for better clinical management of vitiligo.

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Impaired PI3K/Akt Activation-Mediated NF-κB Inactivation Under Elevated TNF-α Is More Vulnerable to Apoptosis in Vitiliginous Keratinocytes

Cited by 60 publications

References 20 publications

Ultrastructural and functional alterations of mitochondria in perilesional vitiligo skin

Ultrastructural and functional alterations of mitochondria in perilesional vitiligo skin

Activation of Eosinophils Interacting with Dermal Fibroblasts by Pruritogenic Cytokine IL-31 and Alarmin IL-33: Implications in Atopic Dermatitis

Novel approaches to vitiligo treatment via modulation of mTOR and NF-κB pathways in human skin melanocytes

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