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.

Highlights

  • Apoptosis is a form of programmed cell death mediated by different stimuli, including binding of TNF-a to death TNFR1 receptor

  • We found that SOCS3 and SOCS1 mRNA and protein expression was substantially higher in IFN-g/ TNF-a-activated keratinocytes obtained from psoriatic patients compared with those isolated from healthy donors (Figure 1a, Po0.01 and Po0.05 for SOCS3 and SOCS1, Figure 1 IFN-g/TNF-a-induced SOCS1 and SOCS3 expression is higher in psoriatic keratinocytes than in healthy cells. (a) Cultured keratinocytes were prepared from healthy skin or from biopsies taken from uninvolved psoriatic skin

  • T cells locally release pro-inflammatory cytokines, such as IFN-g and TNF-a, responsible for the activation of the resident epidermal keratinocytes skin.[26,30]. Because of their intrinsically altered capacity to respond to IFN-g and TNF-a, psoriatic keratinocytes express a plethora of inflammatory mediators, involved in the chronicization of the local immune responses.[26,31]

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Summary

Introduction

Apoptosis is a form of programmed cell death mediated by different stimuli, including binding of TNF-a to death TNFR1 receptor. In the continuously renewing skin tissue, mechanisms of proliferation, differentiation and cell death are tightly regulated to prevent inappropriate and excessive epidermal growth.[16,17] dysfunctional apoptosis can occur in the skin, and it determines the development and chronicization of several skin diseases, in particular in psoriasis In this pathological context, epidermal keratinocytes are characterized by an aberrant resistance to apoptosis, which concurs to the peculiar thickening of psoriatic epidermis.[18] Multiple factors have been proposed to contribute to the reduced susceptibility of keratinocytes to apoptosis, such as their predisposition to express enhanced levels of the antiapoptotic molecules survivin and BCL-XL.[19,20]. We demonstrated that SOCS1 and SOCS3 molecules, both abundantly expressed

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