title: Anti-apoptotic effects of suppressor of cytokine signaling 3 and 1 in psoriasis.
abstract: Because of their genetically determined capacity to respond to pro-inflammatory stimuli, keratinocytes have a crucial role in the pathogenesis of psoriasis. Upon IFN-γ and TNF-α exposure, psoriatic keratinocytes express exaggerated levels of inflammatory mediators, and show aberrant hyperproliferation and terminal differentiation. The thickening of psoriasic skin also results from a peculiar resistance of keratinocytes to cytokine-induced apoptosis. In this study, we investigated on the molecular mechanisms concurring to the resistance of psoriatic keratinocytes to cell death, focusing on the role having suppressor of cytokine signaling (SOCS)1 and SOCS3, two molecules abundantly expressed in IFN-γ/TNF-α-activated psoriatic keratinocytes, in sustaining anti-apoptotic pathways. We found that SOCS1 and SOCS3 suppress cytokine-induced apoptosis by sustaining the activation of the PI3K/AKT pathway in keratinocytes. The latter determines the activation of the anti-apoptotic NF-κB cascade and, in parallel, the inhibition of the pro-apoptotic BAD function in keratinocytes. For the first time, we report that phosphorylated AKT and phosphorylated BAD are strongly expressed in lesional psoriatic skin, compared with healthy or not lesional skin, and they strictly correlate to the high expression of SOCS1 and SOCS3 molecules in the psoriatic epidermis. Finally, the depletion of SOCS1 and SOCS3, as well as the chemical inactivation of PI3K activity in psoriatic keratinocytes, definitively unveils the role of PI3K/AKT cascade on the resistance of diseased keratinocytes to apoptosis.
authors: Laboratory of Experimental Immunology, Istituto Dermopatico dell'Immacolata-IDI-IRCCS, Rome, Italy. madonnastefania@gmail.com
authors: S
authors: S
authors: Madonna
authors: C
authors: C
authors: Scarponi
authors: S
authors: S
authors: Pallotta
authors: A
authors: A
authors: Cavani
authors: C
authors: C
authors: Albanesi
mesh_terms: D017209:Apoptosis; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011565:Psoriasis / Q000378:metabolism*; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D018631:ras Proteins / Q000378:metabolism
chemical_list: D016328:NF-kappa B; C108944:SOCS1 protein, human; C106644:SOCS3 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D007371:Interferon-gamma; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D018631:ras Proteins