IL-17 promotes keratinocyte proliferation via the downregulation of C/EBPα

Abstract

Abstract. Psoriasis vulgaris is a common chronic inflammatory skin disease characterized by the hyperproliferation and abnormal differentiation of keratinocytes. CCATT/enhancer binding protein α (C/EBPα) is abundant in the epidermis and is associated with the proliferation of keratinocytes. However, the role of C/EBPα in the proliferation of keratinocytes and the pathogenesis of psoriasis vulgaris are yet to be elucidated. In the present study, using two-step immunohistochemistry, the expression levels of C/EBPα and Ki-67 were examined in skin biopsies harvested from 30 patients with psoriasis vulgaris and 30 healthy control subjects. The proliferation index (PI) was calculated and the correlation between C/EBPα expression levels and the PI was assessed using Pearson's correlation coefficient. In addition, the effect on HaCaT immortalized human keratinocytic cells of treatment with various concentrations of interleukin (IL)-17 was investigated. Subsequently, cell proliferation rates were examined using a Cell Counting kit-8 assay and the mRNA and protein expression levels of C/EBPα were analyzed using semiquantitative reverse transcription-polymerase chain reaction and western blotting, respectively, in order to analyze the effects of IL-17 stimulation on C/EBPα expression levels. C/EBPα expression was predominantly detected in the cytoplasm of the keratinocytes and C/EBPα expression levels were significantly lower in the psoriatic lesions (P<0.05), as compared with the control group. An inverse correlation was detected between the expression levels of C/EBPα and the PI in the psoriatic lesions. Furthermore, a significant increase in the cell proliferation rate and significant reductions in the mRNA and protein expression levels of C/EBPα were detected in HaCaT cells following treatment with IL-17. These results demonstrated that C/EBPα may act as a downstream target of IL-17 and may be associated with the pathogenesis of psoriasis.

The CCL20 and CCR6 axis in psoriasis

“…The infiltrating dermal dendritic cells produce large amounts of TNF‐α and IL‐23 and induce the differentiation of IL‐17A–producing helper T (Th17) cells (Figure ) . IL‐17A upregulates the proliferation of keratinocytes and downregulates the differentiation of these cells . IL‐17A also upregulates the production of the neutrophil‐attracting cyto‐/chemokines IL‐36, CXCL1, CXCL2 and CXCL8 by keratinocytes .…”

“…24,25 IL-17A upregulates the proliferation of keratinocytes and downregulates the differentiation of these cells. 26,27 IL-17A also upregulates the production of the neutrophil-attracting cyto-/chemokines IL-36, CXCL1, CXCL2 and CXCL8 by keratinocytes. 28,29 Moreover, IL-17A promotes keratinocytes to produce CCL20, which is an essential chemoattractant for CCR6 + Th17 cells.…”

MiR‐486 promotes proliferation and suppresses apoptosis in myeloid cells by targeting Cebpa in vitro

“…Down‐regulating Cebpa by CUGBP1 was reported to promote cell proliferation and suppress apoptosis in human non‐small cell lung cancers . Downregulation of Cebpa by IL‐17 promotes keratinocyte proliferation . It was also reported that the transcription factor Cebpa is a strong inhibitor of cell proliferation through cyclin‐dependent protein kinase 2 (cdk2) and cdk4 .…”

“…25 Downregulation of Cebpa by IL-17 promotes keratinocyte proliferation. 26 It was also reported that the transcription factor Cebpa is a strong inhibitor of cell proliferation through cyclin-dependent protein kinase 2 (cdk2) and cdk4. 27 Overexpression of Cebpa significantly decreased cell proliferation and upregulated the expression levels of the apoptosis-related genes Foxo3 and Bim in K562 cells.…”

Rnai-Mediated Silencing of Matrix Metalloproteinase 1 in Epidermal Keratinocytes Influences the Biological Effects of Interleukin 17a

“…The concentration of IL-17A in the blood serum of healthy volunteers usually does not exceed 10 pg/mL (Shilova et al, 2015). In contrast, the biological effects of IL-17A in cultured epidermal keratinocytes and fibroblasts, such as activation of protein kinases (Peric et al, 2008(Peric et al, , 2009, induction of proinflammatory cytokines (Tohyama et al, 2009;Cho et al, 2012) or influencing cell proliferation (Ma, Jia, 2016) require an incubation of cells in the presence of 10-100 ng/mL IL17-A. Presumably, this difference can be explained by the fact that in psoriasis, T h17 cells, which are the main source of IL17-A in the body, are predominantly located in the inflamed tissue where they are needed to stabilize the inflammatory response.…”