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Tacrolimus Inhibits TNF-α/IL-17A-Produced pro-Inflammatory Effect on Human Keratinocytes by Regulating IκBζ

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Abstract

Psoriasis is a chronic autoimmune disease that is predominantly mediated by T-lymphocytes and keratinocytes. Tacrolimus is T cell-targeted immunosuppression drug that has been widely used in topical therapy of psoriasis; however, the pharmacologic effect of tacrolimus on human keratinocytes has not been fully clarified. This study aimed to investigate the potential regulatory effect of tacrolimus on TNF-α/ IL-17A-costimulated human keratinocytes in the mimic psoriatic microenvironment. The cultured normal human keratinocytes (NHKs) were divided into the following groups: control, TNF-α/IL-17A, tacrolimus, and TNF-α/IL-17A + tacrolimus. Cultured cells and supernatant were collected after 24 h, and then real-time quantitative PCR, western blot, and ELISA analysis were performed. Foreskin tissues were treated by using TNF-α, IL-17A, and tacrolimus 0.03% ointment and then cultured for 24 h, and immunohistochemistry was performed. NHKs expressed significant IL-36γ, CCL-20, IL-1β, S100-A9, and CXCL-1 mRNA after TNF-α/IL-17A treatment. Tacrolimus significantly inhibited TNF-α/IL-17A-induced IL-36γ, CCL-20, IL-1β, and S100-A9 expression at gene level and IL-36γ and CCL-20 expression at protein level. We further discovered TNF-α/IL-17A induced significant IκBζ mRNA and protein expression in NHKs, which could be inhibited by tacrolimus. Tacrolimus can inhibit pro-inflammatory synergistic action of TNF-α/IL-17A on human keratinocytes by regulating IκBζ expression.

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Funding

This work was supported by the National Natural Science Foundation of China (81673062).

Author information

Author notes

  1. YingYing Hu, Jing Guo and Li Yin contributed equally to this work.

Authors and Affiliations

  1. Department of Dermatology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China

    YingYing Hu, Jing Guo, Li Yin, Jie Tu & ZhiQiang Yin

  2. Department of Medical Cosmetology, Wuqing People’s Hospital, Wuqing, China

    YingYing Hu

  3. Department of Dermatology, Zhenjiang First People’s Hospital, Zhenjiang, China

    Jing Guo

  4. Department of Dermatology, Affiliated Wuxi People’s Hospital, Nanjing Medical University, Wuxi, China

    Li Yin

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  1. YingYing Hu
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Contributions

YH and JG were responsible for cell and tissue culture, qRT-PCR, and western blot. LY was responsible for ELISA analysis and immunohistochemistry. JT was responsible for data analysis. ZY was responsible for the quality of the overall manuscript. YH, JG, and LY contributed equally to this work.

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Correspondence to ZhiQiang Yin.

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ESM 1

Real-time quantitative PCR of pro-inflammatory cytokines in NHKs after 30 min and 2 h. statistical significance indicated *P < 0.05 and ***P < 0.001. Abbreviation: NHKs, normal human keratinocytes; TNF-α, tumor necrosis factor α; IL-17A, interleukin-17A; IL-36γ, interleukin-36γ; CCL20, chemokine (C-C motif) ligand 20; IL-1β, Interleukin-1β; S100-A9, S100 calcium-binding protein A9; CXCL1, chemokine (C-X-C motif) ligand 1

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Hu, Y., Guo, J., Yin, L. et al. Tacrolimus Inhibits TNF-α/IL-17A-Produced pro-Inflammatory Effect on Human Keratinocytes by Regulating IκBζ. Inflammation 43, 692–700 (2020). https://doi.org/10.1007/s10753-019-01151-6

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  • DOI: https://doi.org/10.1007/s10753-019-01151-6

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