Calcipotriol Inhibits Proliferation of Human Keratinocytes by Downregulating Stat1 and Stat3 Signaling

Abstract

Psoriasis is an autoimmune disease, which is characterized by aberrantly high levels of inflammation, but the underlying pathogenic mechanisms are still not fully understood. Signal transducer and activator of transcription 1 (STAT1) and STAT3, and the downstream proteins suppressor of cytokine signaling 1 (SOCS1) and SOCS3, have been implicated in psoriasis disease progression. Calcipotriol, a synthetic derivative of vitamin D, has been used clinically to treat psoriasis, but the mechanism of action that underlies the beneficial effects of calcipotriol is still being explored. The objective of this study was to determine whether STAT1 and STAT3 signaling is involved in calcipotriol treatment. Using an in vitro immortal human keratinocyte cell line, HaCaT cells, as a psoriasis model, we examined the molecular signaling induced by calcipotriol treatment. We found that calcipotriol treatment or silencing of either STAT1 or STAT3 inhibited proliferation of HaCaT cells. Calcipotriol downregulated the expression of STAT1 and STAT3 at the messenger RNA (mRNA) and protein levels. The levels of phosphorylated STAT1 and STAT3 were also decreased, suggesting calcipotriol treatment inhibited STAT1 and STAT3 activation. Calcipotriol-mediated STAT inhibition was further substantiated by the downregulation of SOCS1 and SOCS3 at the mRNA and protein expression levels. Taken together, our results suggest a novel molecular mechanism for calcipotriol-mediated treatment effects in psoriasis.

A Water-Soluble Extract from Actinidia arguta Ameliorates Psoriasis-Like Skin Inflammation in Mice by Inhibition of Neutrophil Infiltration

“…Thus, STAT3 has been aroused as an ideal therapeutic target for psoriasis. Indeed, a recent study has shown that calcipotriol, which has been used widely for the treatment of psoriasis, inhibits proliferation of keratinocytes by downregulating phosphorylation of STAT3 [ 32 ]. Our data showed a decrease in epidermal thickness in IMQ-treated mice by topical application of PG102 as well as suppression of proliferation and phosphorylation of tyrosine 705 and serine 727 residues of STAT3 in HaCaT cells.…”

Effect of RNA Interference Targeting STAT3 Gene Combined with Ultrasonic Irradiation and SonoVue Microbubbles on Proliferation and Apoptosis in Keratinocytes of Psoriatic Lesions

“…Previous studies have shown that STAT3 is a key transcriptional factor involved in the regulation of cell proliferation, and the inhibitions of STAT3 phosphorylation or expression can result in decreased proliferation of normal human KCs or HaCaT cells. [ 12 18 ] In our study, STAT3 siRNA inhibited the growth of psoriatic KCs in a time-dependent manner. The siRNA carried by Lipofectamine 3000 combined with ultrasonic irradiation and SonoVue microbubbles showed higher proliferation inhibition compared with that only carried by Lipofectamine 3000.…”

Logical and experimental modeling of cytokine and eicosanoid signaling in psoriatic keratinocytes

“…More specifically, calcipotriol affects mostly differentiation and apoptosis, whereas cPLA 2 ɑ appears to mostly affect proliferation. Calcipotriol is able to have both an antiproliferative ( Kristl et al., 2008 ; Liang et al., 2017 ) and a pro-apoptotic effect ( Huang et al, 2019 ; Tiberio et al., 2009 ) in psoriatic KCs. Apoptosis is subject to an elaborate regulation and controlled by the ratio of pro- to anti-apoptotic regulators, meaning that both types of regulators can be active at the same time ( Jan and Chaudhry, 2019 ).…”