Metformin inhibits proliferation and proinflammatory cytokines of human keratinocytesin vitrovia mTOR-signaling pathway

Abstract

Context: The antidiabetic drug metformin exhibits antiproliferative and pro-apoptotic effects in various cells, suggesting its potential to treat a variety of malignant and non-malignant hyperplastic diseases. Clinical studies indicate that psoriasis patients with metformin treatment have a better response than those without metformin. Objective: The present study evaluates the antiproliferative activity and anti-inflammatory responses of metformin in human keratinocytes in vitro and explores the underlying mechanisms. Materials and methods: HaCaT cells were incubated with metformin at 0, 25, 50, and 100 mM for 48 h. Antiproliferative activity was evaluated by MTT and apoptotic response was examined by flow cytometry. ELISA was used to detect IL-6, TNF-a, and VEGF protein expression. Western blot was used to investigate the expression of the mammalian target of rapamycin (mTOR) and its downstream effectors p70 ribosomal S6 kinase (p70S6K). Results: The survival rates of HaCaT cells treated with metformin at 50 mM were reduced to 75.6, 59.4, and 30.3% at 24, 48, and 72 h, respectively. The number of apoptotic HaCaT cells was significantly increased at 50 mM metformin after 48 h treatment. Metformin can exert an antiinflammatory effect by direct inhibition of IL-6, TNF-a, and VEGF. Metformin at 50 mM significantly reduced the phosphorylation of mTOR and p70S6K, by 49.0 and 62.1%, respectively. Discussion and conclusion: Metformin treatment significantly inhibited proliferation and proinflammatory responses in HaCaT cells by a mechanism associated with inhibition of the mTOR signaling pathway. The results indicate that metformin may be used as a potential therapeutic agent for psoriasis.

Metformin inhibits IL-1β secretion via impairment of NLRP3 inflammasome in keratinocytes: implications for preventing the development of psoriasis

“…Therefore, we examined whether metformin treatment decreased caspase-1 expression using inhibitors of AMPK and SIRT1 in NHEKs. Metformin has been identified as a potent AMPK activator 43 . We examined whether treatment with it induced AMPK phosphorylation in NHEKs, with the results showing that it induced such phosphorylation in a dose-dependent manner (Fig.…”

T helper 17 cell/regulatory T-cell imbalance in hidradenitis suppurativa/acne inversa: the link to hair follicle dissection, obesity, smoking and autoimmune comorbidities

“…Metformin inhibits mTORC1 at various metabolic checkpoints . In HaCaT cells, metformin inhibits mTORC1 activity and the expression of IL‐6 and tumour necrosis factor (TNF)‐α . Metformin attenuates inflammation in murine autoimmune arthritis, graft‐versus‐host disease, IBD and autoimmune encephalomyelitis .…”

“…169 In HaCaT cells, metformin inhibits mTORC1 activity and the expression of IL-6 and tumour necrosis factor (TNF)-a. 170 Metformin attenuates inflammation in murine autoimmune arthritis, 171 graft-versus-host disease, 172 IBD 173 and autoimmune encephalomyelitis. 174 In these models, metformin decreased Th17 cells and increased Treg cell differentiation.…”

Molecular biomarkers in cardiac hypertrophy

“…[13][14][15][16] It has been confirmed that the mammalian target of rapamycin (mTOR) signalling pathway promotes the onset and progression of cardiac growth. [17][18][19][20] MiR-96 is negatively correlated with mTOR and may prevent myocardial hypertrophy by inhibiting mTOR. 20 On the other hand, miR-96 was found to inhibit cardiac hypertrophy by targeting growth factor receptor-bound 2 which is a negative regulator of cardiac hypertrophy.…”