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

Main Article Content

Huanhuan Zhang
Cuimin Ren
Qiang Liu
Qing Wang
Dahu Wang


mice, psoriasis, TEAD4, TFAP2C, Th1, Th17


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.

Abstract 124 | PDF Downloads 116 HTML Downloads 16 XML Downloads 3


1. Gao J, Chen F, Fang H, Mi J, Qi Q, Yang M. Daphnetin inhibits proliferation and inflammatory response in human HaCaT keratinocytes and ameliorates imiquimod-induced psoriasis-like skin lesion in mice. Biol Res. 2020;53(1):48. 10.1186/s40659-020-00316-0

2. Parisi R, Iskandar IYK, Kontopantelis E, Augustin M, Griffiths CEM, Ashcroft DM. National, regional, and worldwide epidemiology of psoriasis: Systematic analysis and modelling study. Br Med J (BMJ) (Clin Res ed.). 2020;369:m1590. 10.1136/bmj.m1590

3. Al-Zubi M, Seetan K, Jarrar B, Aldebei A, Rubbai Y, Daradkeh S. Evaluation of sex hormone profiles and seminal fluid analysis in psoriatic patients and their correlation with psoriasis severity. J Men’s Health (JOMH). 2022;18(2):28. 10.31083/jomh.2021.075

4. Ghoreschi K, Balato A, Enerbäck C, Sabat R. Therapeutics targeting the IL-23 and IL-17 pathway in psoriasis. Lancet. 2021;397(10275):754–66. 10.1016/S0140-6736(21)00184-7

5. Li XQ, Chen Y, Dai GC, Zhou BB, Yan XN, Tan RX. Abietic acid ameliorates psoriasis-like inflammation and modulates gut microbiota in mice. J Ethnopharmacol. 2021;272:113934. 10.1016/j.jep.2021.113934

6. Cheng L, Wang S, Peng C, Zou X, Yang C, Mei H, et al. Human umbilical cord mesenchymal stem cells for psoriasis: A phase 1/2a, single-arm study. Signal Transduct Targeted Ther. 2022;7(1):263. 10.1038/s41392-022-01059-y

7. Saygın H, Tosun M, Öztürk A, Ergin İE, Kıraç E, Asdemir A, et al. Effects of psoriasis and metabolic syndrome on male sexual functions. J Men’s Health (JOMH). 2021;17(3):91–5. 10.31083/jomh.2021.038

8. Walter K. Psoriasis. JAMA. 2022;327(19):1936. 10.1001/jama.2022.5270

9. Nguyen LTH, Choi MJ, Shin HM, Yang IJ. Coptisine alleviates imiquimod-induced psoriasis-like skin lesions and anxiety-like behavior in mice. Molecules (Basel, Switzerland). 2022;27(4):1412. 10.3390/molecules27041412

10. Pastor WA, Liu W, Chen D, Ho J, Kim R, Hunt TJ, et al. TFAP2C regulates transcription in human naive pluripotency by opening enhancers. Nature Cell Biol. 2018;20(5):553–64. 10.1038/s41556-018-0089-0

11. Aqeilan RI, Palamarchuk A, Weigel RJ, Herrero JJ, Pekarsky Y, Croce CM. Physical and functional interactions between the Wwox tumor suppressor protein and the AP-2 gamma transcription factor. Cancer Res. 2004;64(22):8256–61. 10.1158/0008-5472.CAN-04-2055

12. Jiang X, Guo S, Xu M, Ma B, Liu R, Xu Y, et al. TFAP2C-mediated lncRNA PCAT1 inhibits ferroptosis in docetaxel-resistant prostate cancer through c-Myc/miR-25-3p/SLC7A11 signaling. Front Oncol. 2022;12:862015. 10.3389/fonc.2022.862015

13. Xing J, Chen W, Chen K, Zhu S, Lin F, Qi Y, et al. TFAP2C knockdown sensitizes bladder cancer cells to cisplatin treatment via regulation of EGFR and NF-κB. Cancers (Basel). 2022;14(19):4809. 10.3390/cancers14194809

14. Gu Z, Zhou Y, Cao C, Wang X, Wu L, Ye Z. TFAP2C-mediated LINC00922 signaling underpins doxorubicin-resistant osteosarcoma. Biomed Pharmacother. 2020;129:110363. 10.1016/j.biopha.2020.110363

15. Do H, Kim D, Kang J, Son B, Seo D, Youn H, et al. TFAP2C increases cell proliferation by downregulating GADD45B and PMAIP1 in non-small cell lung cancer cells. Biol Res. 2019;52(1):35. 10.1186/s40659-019-0244-5

16. Fang F, Yuan Q. Anlotinib inhibits the proliferation, migration and invasion, and induces apoptosis of breast cancer cells by downregulating TFAP2C. Oncol Lett. 2022;23(2):46. 10.3892/ol.2021.13164

17. Sharma N, Kubaczka C, Kaiser S, Nettersheim D, Mughal SS, Riesenberg S, et al. Tpbpa-Cre-mediated deletion of TFAP2C leads to deregulation of Cdkn1a, Akt1 and the ERK pathway, causing placental growth arrest. Development (Cambridge, England). 2016;143(5):787–98. 10.1242/dev.128553

18. Fagerberg L, Hallström BM, Oksvold P, Kampf C, Djureinovic D, Odeberg J, et al. Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Mol Cell Proteomics (MCP). 2014;13(2):397–406. 10.1074/mcp.M113.035600

19. Wang Y, Chen S, Jiang Q, Deng J, Cheng F, Lin Y, et al. TFAP2C facilitates somatic cell reprogramming by inhibiting c-Myc-dependent apoptosis and promoting mesenchymal-to-epithelial transition. Cell Death Dis. 2020;11(6):482. 10.1038/s41419-020-2684-9

20. Gadkar V, Filion M. New developments in quantitative real-time polymerase chain reaction technology. Curr Issues Mol Biol. 2014;16:1–6. Epub 2013 April 8.

21. Zucha D, Kubista M, Valihrach L. Tutorial: Guidelines for single-cell RT-qPCR. Cells. 2021;10(10):2607. 10.3390/cells10102607

22. Rahmati M, Shariatzadeh Joneydi M, Koyanagi A, Yang G, Ji B, Won Lee S, et al. Resistance training restores skeletal muscle atrophy and satellite cell content in an animal model of Alzheimer’s disease. Sci Rep. 2023;13(1):2535. 10.1038/s41598-023-29406-1

23. Rahmati M, Taherabadi SJ. The effects of exercise training on kinesin and GAP-43 expression in skeletal muscle fibers of STZ-induced diabetic rats. Sci Rep. 2021;11(1):9535. 10.1038/s41598-021-89106-6

24. Bostani M, Rahmati M, Mard SA. The effect of endurance training on levels of LINC complex proteins in skeletal muscle fibers of STZ-induced diabetic rats. Sci Rep. 2020;10(1):8738. 10.1038/s41598-020-65793-5

25. Rahmati M, Rashno A. Automated image segmentation method to analyse skeletal muscle cross section in exercise-induced regenerating myofibers. Sci Rep. 2021;11(1):21327. 10.1038/s41598-021-00886-3

26. Kim D, Kim HJ, Baek JO, Roh JY, Jun HS. Lysophosphatidic acid mediates imiquimod-induced psoriasis-like symptoms by promoting keratinocyte proliferation through LPAR1/ROCK2/PI3K/AKT signaling pathway. Int J Mol Sci. 2021;22(19):10777. 10.3390/ijms221910777

27. Zhong L, Luo N, Zhong X, Xu T, Hao P. The immunoregulatory effects of natural products on psoriasis via its action on Th17 cells versus regulatory T cells balance. Int Immunopharmacol. 2022;110:109032. 10.1016/j.intimp.2022.109032

28. Greb JE, Goldminz AM, Elder JT, Lebwohl MG, Gladman DD, Wu JJ, et al. Psoriasis. Nature Rev Dis Primers. 2016;2:16082. 10.1038/nrdp.2016.82

29. Cho Y-d, Choi S-h, Park S-j, Yu W-s, Cho H-j, Kim K-h, et al. The effects of oxygen and medicines on T cells in hypoxic co-culture. Signa Vitae. 2021;17(6):43–51. 10.22514/sv.2021.103

30. Krueger JG. Hiding under the skin: A welcome surprise in psoriasis. Nature Med. 2012;18(12):1750–1. 10.1038/nm.3025

31. Gordon KB, Gottlieb AB, Langely RG, van de Kerkhof P, Belasco KT, Sundaram M, et al. Adalimumab retreatment successfully restores clinical response and health-related quality of life in patients with moderate to severe psoriasis who undergo therapy interruption. J Eur Acad Dermatol Venereol (JEADV). 2015;29(4):767–76. 10.1111/jdv.12677

32. Michalak-Stoma A, Bartosińska J, Raczkiewicz D, Kowal M, Kozak J, Gujski M, et al. Multiple cytokine analysis of Th1/Th2/Th9/Th17/Th22/Treg cytokine pathway for individual immune profile assessment in patients with psoriasis. Med Sci Monit Int Med J Exp Clin Res. 2022;28:e938277. 10.12659/MSM.938277

33. Hsu SC, Lin CY, Lin YY, Collins CC, Chen CL, Kung HJ. TEAD4 as an oncogene and a mitochondrial modulator. Front Cell Dev Biol. 2022;10:890419. 10.3389/fcell.2022.890419

34. Huh HD, Kim DH, Jeong HS, Park HW. Regulation of TEAD transcription factors in cancer biology. Cells. 2019;8(6):600. 10.3390/cells8060600

35. Jiang SW, Desai D, Khan S, Eberhardt NL. Cooperative binding of TEF-1 to repeated GGAATG-related consensus elements with restricted spatial separation and orientation. DNA Cell Biol. 2000;19(8):507–14. 10.1089/10445490050128430

36. Chen M, Huang B, Zhu L, Chen K, Liu M, Zhong C. Structural and functional overview of TEAD4 in cancer biology. OncoTargets Ther. 2020;13:9865–74. 10.2147/OTT.S266649

37. Guo Y, Zhu Z, Huang Z, Cui L, Yu W, Hong W, et al. CK2-induced cooperation of HHEX with the YAP-TEAD4 complex promotes colorectal tumorigenesis. Nature Comm. 2022;13(1):4995. 10.1038/s41467-022-32674-6

38. Liu H, Zhang S, Liu Y, Ma J, Chen W, Yin T, et al. Knockdown of HSP110 attenuates hypoxia-induced pulmonary hypertension in mice through suppression of YAP/TAZ-TEAD4 pathway. Respiratory Res. 2022;23(1):209. 10.1186/s12931-022-02124-4

39. Bhat IP, Rather TB, Bhat GA, Maqbool I, Akhtar K, Rashid G, et al. TEAD4 nuclear localization and regulation by miR-4269 and miR-1343-3p in colorectal carcinoma. Pathol Res Pract. 2022;231:153791. 10.1016/j.prp.2022.153791