Mammalian target of rapamycin and its downstream signalling components are activated in psoriatic skin

Buerger, Claudia; Malisiewicz, Bartosz; Eiser, A.; Hardt, Katja; Boehncke, Wolf‐Henning

doi:10.1111/bjd.12271

Cited by 71 publications

(81 citation statements)

References 16 publications

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“…The study population comprised 28 patients with psoriasis and 10 healthycontrols.Of28patients,fiveunderwentanti-TNF-α therapy with previous data [4,7] thatactivationofmTORsignallingmightbe involved in psoriasis pathogenesis and confirm its increasing relevanceinskininflammatoryprocess. [8] Furthermore,nodifferences Abbreviations:HS,healthyskin;LS,lesionalskin;mTORC,mTORsignallingcomplex;mTOR,mechanistictargetofrapamycin;NLS,non-lesionalskin;P-S6K1,phospho-S6-ribosomalprotein;…”

Section: Experimental Designsupporting

confidence: 64%

“…[2] WefoundthatS6K1and,inparticular,itsactivatedformPS6K1wereslightlypresentinhealthyskinbutstronglyatpsoriatic plaquelevelinaccordancewithBurgeretal., [7] suggestingthespe- and insulin resistance [9] (s7-S9). In this study, we showed, for the first time, that P-S6K1 was completely abolished after 12weeks of etanercept therapy, whereas it was still expressed after systemicretinoidtreatment,indicatingastrongeractionofanti-TNF-α agentonmTORC1.PreviousevidenceshowedthatsilencingmTOR leads to the inhibition of TNF-α-induced P-S6K1 (s10).…”

Section: Discussionmentioning

confidence: 99%

“…[4,7] Up tonow,thelinkbetweenmTORC1andTNF-α in psoriasis has not beenyetelucidatedeventhoughitiswellknownthatTNF-α is an upstream signal of mTORC1 and also one of main protagonists of the disease.…”

Section: Introductionmentioning

confidence: 99%

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Mechanistic target of rapamycin complex 1 is involved in psoriasis and regulated by anti‐TNF‐α treatment

Balato

Lembo

Ayala

et al. 2017

Experimental Dermatology

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The mechanistic target of rapamycin (mTOR) acts through two distinct signalling complexes,\ud known as mTOR complex (mTORC) 1 and mTORC2. One of the main upstream regulator of\ud mTORC1 is tumour necrosis factor (TNF)-α, an important pro-inflammatory cytokine involved in\ud psoriasis. When active, mTORC1 phosphorylates and activates its downstream effector ribosomal protein S6 kinase 1 (S6K1) which is also found increased in psoriasis. Thus, the aim of the study\ud was to assess the involvement of mTORC1 signalling as well as to shed a light on the possible\ud relationship between mTORC1 and TNF-α in psoriasis. Our results showed that mTOR, S6K1 and,\ud in particular, its active form P-S6K1 were increased in psoriatic plaque, suggesting a specific\ud involvement of mTORC1 pathway in the disease. Moreover, for the first time, we reported that PS6K1\ud was completely abolished after anti-TNF-α therapy, indicating a stronger action of anti-TNF-\ud α agent on mTORC1

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Section: Experimental Designsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 99%

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Mechanistic target of rapamycin complex 1 is involved in psoriasis and regulated by anti‐TNF‐α treatment

Balato

Lembo

Ayala

et al. 2017

Experimental Dermatology

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“…Buerger et al found that mTOR and its downstream signaling molecule, the ribosomal S6 kinase, were upregulated in lesional psoriatic skin, suggesting a role of mTOR signaling in psoriatic epidermal proliferation (Buerger et al, 2013). mTOR inhibitors may offer a range of new therapeutic options for psoriasis patients.…”

Section: Discussionmentioning

confidence: 99%

Metformin inhibits proliferation and proinflammatory cytokines of human keratinocytesin vitrovia mTOR-signaling pathway

Liu

Yang

et al. 2015

Pharmaceutical Biology

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Context: The antidiabetic drug metformin exhibits antiproliferative and pro-apoptotic effects in various cells, suggesting its potential to treat a variety of malignant and non-malignant hyperplastic diseases. Clinical studies indicate that psoriasis patients with metformin treatment have a better response than those without metformin. Objective: The present study evaluates the antiproliferative activity and anti-inflammatory responses of metformin in human keratinocytes in vitro and explores the underlying mechanisms. Materials and methods: HaCaT cells were incubated with metformin at 0, 25, 50, and 100 mM for 48 h. Antiproliferative activity was evaluated by MTT and apoptotic response was examined by flow cytometry. ELISA was used to detect IL-6, TNF-a, and VEGF protein expression. Western blot was used to investigate the expression of the mammalian target of rapamycin (mTOR) and its downstream effectors p70 ribosomal S6 kinase (p70S6K). Results: The survival rates of HaCaT cells treated with metformin at 50 mM were reduced to 75.6, 59.4, and 30.3% at 24, 48, and 72 h, respectively. The number of apoptotic HaCaT cells was significantly increased at 50 mM metformin after 48 h treatment. Metformin can exert an antiinflammatory effect by direct inhibition of IL-6, TNF-a, and VEGF. Metformin at 50 mM significantly reduced the phosphorylation of mTOR and p70S6K, by 49.0 and 62.1%, respectively. Discussion and conclusion: Metformin treatment significantly inhibited proliferation and proinflammatory responses in HaCaT cells by a mechanism associated with inhibition of the mTOR signaling pathway. The results indicate that metformin may be used as a potential therapeutic agent for psoriasis.

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“…Several proteins have been associated with these mechanisms like BCL2, BAX, NFATC1, PPARδ, EGF, mTOR, NF-κB etc. [137][138][139][140] Most of them could be found in the group of central proteins detected by DEG-derived network analysis. Unpublished DEG-coded proteins with potential role in hyperproliferation, like CCNA2, TFDP1 and MECOM, were also found (Table 3).…”

Section: Psoriasismentioning

confidence: 99%

High Throughput Screening of Gene Expression for the Investigation of Multifactorial Dermatological Disorders

Manczinger¹

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Mammalian target of rapamycin and its downstream signalling components are activated in psoriatic skin

Abstract: Altogether these results suggest a role for mTOR signalling in the epidermal changes leading to the psoriatic phenotype. mTOR inhibition might be a mode of action to explore in developing innovative antipsoriatic drugs.

Cited by 71 publications

References 16 publications

Mechanistic target of rapamycin complex 1 is involved in psoriasis and regulated by anti‐TNF‐α treatment

Mechanistic target of rapamycin complex 1 is involved in psoriasis and regulated by anti‐TNF‐α treatment

Metformin inhibits proliferation and proinflammatory cytokines of human keratinocytesin vitrovia mTOR-signaling pathway

High Throughput Screening of Gene Expression for the Investigation of Multifactorial Dermatological Disorders

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