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  2. Inhibition of JAK1/STAT3 pathway by 2-methoxyestradiol ameliorates psoriatic features in vitro and in an imiquimod-induced psoriasis-like mouse model

Inhibition of JAK1/STAT3 pathway by 2-methoxyestradiol ameliorates psoriatic features in vitro and in an imiquimod-induced psoriasis-like mouse model

  • Eur J Pharmacol. 2022 Oct 15;933:175276. doi: 10.1016/j.ejphar.2022.175276.
Jiaxuan Tang 1 Chaofan Liu 1 Shiying Liu 1 Xing Zhou 2 Jinghao Lu 3 Ming Li 1 Lubing Zhu 4
Affiliations

Affiliations

  • 1 Department of Dermatology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China.
  • 2 Department of Dermatology, Shanghai Children's Hospital, Shanghai Jiao Tong University, 355 Luding Road, Shanghai, 200062, China.
  • 3 Department of Dermatology, Huashan Hospital, Fudan University, 12 Wulumuqi Middle Road, Shanghai, 200040, China.
  • 4 Department of Dermatology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China. Electronic address: [email protected].
Abstract

Psoriasis is characterized by hyperproliferative keratinocytes, dilated capillaries and leukocyte infiltration. 2-Methoxyestradiol (2-ME) has shown significant inhibition on proliferation, angiogenesis and inflammation. To evaluate the anti-psoriatic potential of 2-ME, psoriasis-like dermatitis was induced by topical application of imiquimod (IMQ) on the dorsal skin of C57BL/6 mice for seven consecutive days, followed by treatment of vehicle or 2-ME ointment from Day 4 on. The psoriasis area and severity index (PASI) was assessed daily. On Day 8, skin histology and spleen index were assessed. The effects of 2-ME on the proliferation, Apoptosis, cell cycle, vascular endothelial growth factor A (VEGFA), and Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathways of HaCaT cells stimulated by interleukin-17 (IL-17A) were detected, together with its effect on the proliferation, tube formation and VEGF receptor expression of human umbilical vein endothelial cells (HUVECs). We found that topical 2-ME treatment significantly improved IMQ-induced psoriasis-like dermatitis and decreased the PASI scores, the activation of STAT3 in the skin (P < 0.05), and the spleen index in mice (P < 0.01). In vitro, 2-ME inhibited the proliferation of HaCaT cells by inducing Apoptosis and G2/M phase arrest (P < 0.01). Moreover, 2-ME suppressed IL-17A-induced VEGFA (2.5 μM: P < 0.05; 5 μM: P < 0.01) and phosphorylation of STAT3 by blocking p-JAK1 in HaCaT cells and prevented tube formation (P < 0.01) and proliferation by targeting VEGF receptors 1 (VEGFR1/Flt-1) and 2 (VEGFR2/KDR/Flk-1) in HUVECs. We conclude that 2-ME alleviated psoriasis in vivo and in vitro by inhibiting JAK1/STAT3 pathway and was a promising therapeutic agent for psoriasis.

Keywords

2-Methoxyestradiol; Angiogenesis; Imiquimod; Inflammation; Keratinocyte; Psoriasis.

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