STAT1 expression and activation is increased in lesional psoriatic skin

Hald, A.; Andrés, Rosa; Salskov-Iversen, Maria L.; Kjellerup, R.B.; Iversen, Lars; Johansen, Claus

doi:10.1111/bjd.12049

Cited by 84 publications

(61 citation statements)

References 28 publications

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“…Aberrant IFN-g production and STAT1 activation are typically found in psoriatic lesions (33)(34)(35)(36). It is speculated that the IFN-g response is derived from Th1 cells.…”

Section: Discussionmentioning

confidence: 99%

Macrophage Migration Inhibitory Factor Triggers Chemotaxis of CD74+CXCR2+ NKT Cells in Chemically Induced IFN-γ–Mediated Skin Inflammation

Hsieh

Chen

Lin

et al. 2014

The Journal of Immunology

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IFN-γ mediates chemically induced skin inflammation; however, the mechanism by which IFN-γ–producing cells are recruited to the sites of inflammation remains undefined. Secretion of macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, from damaged cells may promote immune cell recruitment. We hypothesized that MIF triggers an initial step in the chemotaxis of IFN-γ–producing cells in chemically induced skin inflammation. Using acute and chronic models of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin inflammation in mouse ears, MIF expression was examined, and its role in this process was investigated pharmacologically. The cell populations targeted by MIF, their receptor expression patterns, and the effects of MIF on cell migration were examined. TPA directly caused cytotoxicity accompanied by MIF release in mouse ear epidermal keratinocytes, as well as in human keratinocytic HaCaT cells. Treatment with the MIF antagonist (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester considerably attenuated TPA-induced ear swelling, leukocyte infiltration, epidermal cell proliferation, and dermal angiogenesis. Inhibition of MIF greatly diminished the dermal infiltration of IFN-γ+ NKT cells, whereas the addition of exogenous TPA and MIF to NKT cells promoted their IFN-γ production and migration, respectively. MIF specifically triggered the chemotaxis of NKT cells via CD74 and CXCR2, and the resulting depletion of NKT cells abolished TPA-induced skin inflammation. In TPA-induced skin inflammation, MIF is released from damaged keratinocytes and then triggers the chemotaxis of CD74+CXCR2+ NKT cells for IFN-γ production.

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“…Aberrant IFN-g production and STAT1 activation are typically found in psoriatic lesions (33)(34)(35)(36). It is speculated that the IFN-g response is derived from Th1 cells.…”

Section: Discussionmentioning

confidence: 99%

Macrophage Migration Inhibitory Factor Triggers Chemotaxis of CD74+CXCR2+ NKT Cells in Chemically Induced IFN-γ–Mediated Skin Inflammation

Hsieh

Chen

Lin

et al. 2014

The Journal of Immunology

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“…Previous studies have shown both an increased expression of STAT1 in psoriatic skin and an increased STAT1 activity as measured by elevated phosphorylation levels of STAT1 (Tyr701) and STAT1(Ser727), which suggests that STAT1 plays a role in the pathogenesis of psoriasis [5,7,30]. Furthermore, STAT1 is known to play an essential role in the regulation of IFNα-induced genes by forming a heterotrimer with STAT2 and IRF9, a transcription factor complex known as IFN-stimulated gene factor 3 (ISGF3).…”

Section: Discussionmentioning

confidence: 99%

“…Advances in our understanding of the role of intracellular signaling in psoriatic inflammation have led to the recognition that many key psoriatic cytokines converge on and initiate intracellular signaling through specific pathways [1,3]. One such intracellular signaling pathway, which is believed to play a key role in the pathogenesis of psoriasis is the JAK/STAT signaling pathway [4][5][6][7]. Chang et al showed that a a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 small molecule inhibitor of JAK3 markedly attenuated of skin lesions following 6 weeks of treatment in the CD18 mutant PL/J mice T cell-dependent psoriasis-form model [8].…”

Section: Introductionmentioning

confidence: 99%

344 STAT2 is involved in the pathogenesis of psoriasis by promoting CXCL11 and CCL5 production by keratinocytes

Johansen

Hald

Bertelsen

et al. 2016

Journal of Investigative Dermatology

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The JAK/STAT signaling pathway is suggested to play an important role in the pathogenesis of psoriasis, and recently JAK/STAT inhibitors have shown promising results in psoriasis treatment. The present study aimed to characterize the role of STAT2 in psoriasis. We demonstrated an increased expression of STAT2 and an increased level of phosphorylated/activated STAT2 in lesional compared with nonlesional psoriatic skin. Gene silencing of STAT2 by siRNA in human keratinocytes revealed that upon IFNα stimulation CXCL11 and CCL5 were the only two cytokines, among 102 analyzed, found to be regulated through a STAT2-dependent mechanism. Moreover, the regulation of CXCL11 and CCL5 depended on IRF9, but not on STAT1 and STAT6. The CXCL11 and CCL5 expression was increased in lesional compared with nonlesional psoriatic skin, and analysis demonstrated positive correlation between the expression of CXCL11 and IFNγ and between the expression of CCL5 and IFNγ in lesional psoriatic skin. In contrast, no correlation between the expression of CXCL11 and IL-17A and the expression of CCL5 and IL-17A in lesional psoriatic skin was found. Our data suggest that STAT2 plays a role in the psoriasis pathogenesis by regulating the expression of CXCL11 and CCL5, and thereby attracting IFNγ-producing immune cells to the skin.

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“…Korábban Hald és munkatársai leírták az aktivált STAT1 kifejezôdését pikkelysömörös tünetes bôrben (17). Kutatócsoportunk megállapította, hogy a STAT1 aktív állapotban van jelen az egész-séges és a pikkelysömörös tüne-tes bôrben egyaránt, ellentétben a tünetmentes bôrrel, ahol jórészt inaktív formában található (18).…”

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Abnormális STAT1 aktivitás pikkelysömörben

Gubán¹,

Kui²,

Képíró³

et al. 2016

BVSZ

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ÖSSZEFOGLALÁS Key words: psoriasis -STAT1-non-lesional skinA pikkelysömör egy multifaktoriális, krónikus bôrbe-tegség, amelynek kialakulásában és fenntartásában mind a veleszületett, mind az adaptív immunitás szerepet ját-szik (1). A pikkelysömörös bôrben az epidermális keratinociták túlzott proliferációja és abnormális differenciá-ciója figyelhetô meg, mely megvastagodott epidermiszt, csökkent vagy hiányzó granuláris réteget eredményez. Emellett fokozottan infiltrálódó T-limfociták, neutrofilek és leukociták, emelkedett növekedési faktor, citokin és kemokin kifejezôdés figyelhetô meg pikkelysömörös tü-netes bôrben a celluláris immunrendszer aberráns aktivá-ciójának köszönhetôen (2-4). A makroszkópikusan normális fenotípust mutató, tünetmentes pikkelysömörös bôr -saját és más kutatócsoportok eredményei szerintkülönbözô eltéréseket hordoz magában az egészségeshez képest (5, 6).A kutatások szerint a pikkelysömör patogenezisében kulcsfontosságú szerepet töltenek be a JAK (Janus kináz) -STAT (signal transducer and activator of transcription) jelátviteli útvonalak, amelyek transzkripciós faktorai abnormális expressziót és aktivációt mutatnak, ezzel hozzá-járulnak a pikkelysömör gyulladásos folyamatainak kialakulásához (7,8). A különbözô JAK-ok (JAK1, JAK2, JAK3, Tyk2) eltérô STAT fehérjékkel tudnak kapcsolatba lépni. A STAT család 7 egymással nagyfokú homológiát mutató tagból áll (STAT 1, 2, 3, 4, 5a, 5b és 6), specifikus aktivitást mutatnak, így a funkciójuk széles skálája figyelhetô meg a JAK-STAT jelátviteli útvonalakon keresztül (9, 10). Számos gént képesek aktiválni, míg másokat gá-tolni, ezáltal hatással vannak olyan alapvetô celluláris folyamatokra, mint a sejtproliferáció és -differenciáció, a sejttúlélés, az apoptózis, a migráció és az angiogenezis (9). Aktivációjuk és deaktivációjuk precízen irányított, né-hány óra alatt lezajló folyamat (11).A STAT1 aktiválódása az interferon (IFN) két külön-bözô típusa, az IFNα és az IFNγ által valósul meg, ame-18

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STAT1 expression and activation is increased in lesional psoriatic skin

Cited by 84 publications

References 28 publications

Macrophage Migration Inhibitory Factor Triggers Chemotaxis of CD74+CXCR2+ NKT Cells in Chemically Induced IFN-γ–Mediated Skin Inflammation

Macrophage Migration Inhibitory Factor Triggers Chemotaxis of CD74+CXCR2+ NKT Cells in Chemically Induced IFN-γ–Mediated Skin Inflammation

344 STAT2 is involved in the pathogenesis of psoriasis by promoting CXCL11 and CCL5 production by keratinocytes

Abnormális STAT1 aktivitás pikkelysömörben

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