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Intracellular Insulin-like growth factor binding protein 2 (IGFBP2) contributes to the senescence of keratinocytes in psoriasis by stabilizing cytoplasmic p21.
- Source :
-
Aging [Aging (Albany NY)] 2020 Apr 17; Vol. 12 (8), pp. 6823-6851. Date of Electronic Publication: 2020 Apr 17. - Publication Year :
- 2020
-
Abstract
- Psoriasis is a chronic Th1/Th17 lymphocytes-mediated inflammatory skin disease, in which epidermal keratinocytes exhibit a peculiar senescent state, resistance to apoptosis and the acquisition of senescence-associated secretory phenotype (SASP). SASP consists of the release of soluble factors, including IGFBPs, that exert extracellular and intracellular functions in IGF-dependent or independent manner.In this report, we investigated the expression and function of IGFBP2 in senescent keratinocytes isolated from the skin of patients with plaque psoriasis. We found that IGFBP2 is aberrantly expressed and released by these cells in vivo , as well as in vitro in keratinocyte cultures undergoing progressive senescence, and it associates with the cyclin-dependent kinase inhibitors p21 and p16 expression. For the first time, we provide evidence for a dual action of IGFBP2 in psoriatic keratinocytes during growth and senescence processes. While extracellular IGFBP2 counter-regulates IGF-induced keratinocyte hyper-proliferation, intracellular IGFBP2 inhibits apoptosis by interacting with p21 and protecting it from ubiquitin-dependent degradation. Indeed, we found that cytoplasmic p21 sustains anti-apoptotic processes, by inhibiting pro-caspase 3 cleavage and JNK phosphorylation in senescent psoriatic keratinocytes. As a consequence, abrogation of p21, as well as that of IGFBP2, found to stabilize cytoplasmic p21 levels, lead to the restoration of apoptosis mechanisms in psoriatic keratinocytes, commonly observed in healthy cells.
- Subjects :
- Adult
Aged
Apoptosis
Biopsy
CDC2 Protein Kinase genetics
Cell Proliferation
Cells, Cultured
Cellular Senescence
Cyclin A1 genetics
Cytoplasm metabolism
Gene Expression
Humans
Middle Aged
Phosphorylation
Psoriasis metabolism
Psoriasis pathology
RNA, Messenger metabolism
Skin metabolism
Up-Regulation
Cyclin-Dependent Kinase Inhibitor p16 metabolism
Cyclin-Dependent Kinase Inhibitor p21 metabolism
Insulin-Like Growth Factor Binding Protein 2 genetics
Insulin-Like Growth Factor Binding Protein 2 metabolism
Keratinocytes physiology
Psoriasis genetics
Skin pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1945-4589
- Volume :
- 12
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Aging
- Publication Type :
- Academic Journal
- Accession number :
- 32302288
- Full Text :
- https://doi.org/10.18632/aging.103045