TFAP2C exacerbates psoriasis-like inflammation by promoting Th17 and Th1 cells activation through regulating TEAD4 transcription

Huanhuan Zhang; Cuimin Ren; Qiang Liu; Qing Wang; Dahu Wang

doi:10.15586/aei.v51i3.854

Huanhuan Zhang

Department of Dermatology, the Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.

Cuimin Ren

Department of Dermatology, the Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.

Qiang Liu

Department of Dermatology, the Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.

Qing Wang

Department of Dermatology, the Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.

Dahu Wang

Department of Dermatology, the Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.

Keywords

mice, psoriasis, TEAD4, TFAP2C, Th1, Th17

Abstract

Background: Psoriasis is one of the chronic and autoimmune skin diseases. It is important to uncover the mechanisms underlying the psoriasis. Transcription factor activator protein (TFAP-2) gamma, also known as AP2-gamma, is a protein encoded by the TFAP2C gene. Immune-mediated pathophysiological processes could be linked to psoriasis, but the mechanism is still unclear. Therefore, to date the cause of psoriasis has not been understood completely.

Materials and methods: Psoriasis is a complex disease triggered by genetic, immunological, and environmental stimuli. Keratinocytes play an important role in both initiation and maintenance phases of psoriasis. A psoriatic keratinocyte model was established by stimulating high sensitivity of human epidermal keratinocytes (HaCaT) to topoisomerase inhibitor cell lines using the accumulation of M5 cytokines comprising interleukin (IL)-17A, IL-22, oncostatin M, IL-1α, and tumor necrosis factor-α (TNF-α). The TFAP2C and transcriptional enhanced associate domain 4 (TEAD4) genes expression was evaluated by reverse transcription-quantitative polymerase chain reaction. Western blot analysis was used to examine protein expression. Cell viability (quantitative) of keratinocytes, including cytotoxicity, proliferation, and cell activation, was evaluated by the MTT assay. The relative percentage values of interleukin (IL)-17a, interferon gamma, and IL-4+ cells were measured by flow cytometry. Accordingly, chromatin immunoprecipitation and luciferase reporter assays were applied to evaluate the binding affinity of TFAP2C and TEAD4 promoter.

Results: Level of the TFAP2C gene was elevated in the lesional skin of psoriasis patients. On the other hand, silencing of the TFAP2C gene suppressed the proliferation and inflammatory response in M5-induced keratinocytes. In addition, inhibition of TFAP2C alleviated imiquimod (IMQ)-induced skin injury in mice model. We also observed that suppression of TFAP2C inhibited the activation of T-helper 17 (Th17) and Th1 cells in IMQ-induced mice model. Mechanically, TFAP2C promoted TEAD4 transcriptional activation.

Conclusion: TFAP2C exacerbated psoriasis-like inflammation by increasing the activation of Th17 and Th1 cells by regulating TEAD4 transcription. This finding clearly indicated that TFAP2C could be considered a valuable biomarker for the prevention and treatment for psoriasis.

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