Glycogen Synthase Kinase-3β Facilitates Cytokine Production in 12-O-Tetradecanoylphorbol-13-Acetate/Ionomycin-Activated Human CD4<sup>+</sup> T Lymphocytes
Cytokines are the major immune regulators secreted from activated CD4<sup>+</sup> T lymphocytes that activate adaptive immunity to eradicate nonself cells, including pathogens, tumors, and allografts. The regulation of glycogen synthase kinase (GSK)-3β, a serine/threonine kinase, control...
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MDPI AG
2020-06-01
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| Online Access: | https://www.mdpi.com/2073-4409/9/6/1424 |
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| author | Cheng-Chieh Tsai Chin-Kun Tsai Po-Chun Tseng Chiou-Feng Lin Chia-Ling Chen |
| author_facet | Cheng-Chieh Tsai Chin-Kun Tsai Po-Chun Tseng Chiou-Feng Lin Chia-Ling Chen |
| author_sort | Cheng-Chieh Tsai |
| collection | DOAJ |
| description | Cytokines are the major immune regulators secreted from activated CD4<sup>+</sup> T lymphocytes that activate adaptive immunity to eradicate nonself cells, including pathogens, tumors, and allografts. The regulation of glycogen synthase kinase (GSK)-3β, a serine/threonine kinase, controls cytokine production by regulating transcription factors. The artificial in vitro activation of CD4<sup>+</sup> T lymphocytes by a combination of 12-O-tetradecanoylphorbol-13-acetate and ionomycin, the so-called T/I model, led to an inducible production of cytokines, such as interferon-γ, tumor necrosis factor-α, and interleukin-2. As demonstrated by the approaches of pharmacological targeting and genetic knockdown of GSK-3β, T/I treatment effectively caused GSK-3β activation followed by GSK-3β-regulated cytokine production. In contrast, pharmacological inhibition of the proline-rich tyrosine kinase 2 and calcineurin signaling pathways blocked cytokine production, probably by deactivating GSK-3β. The blockade of GSK-3β led to the inhibition of the nuclear translocation of T-bet, a vital transcription factor of T lymphocyte cytokines. In a mouse model, treatment with the GSK-3β inhibitor 6-bromoindirubin-3’-oxime significantly inhibited T/I-induced mortality and serum cytokine levels. In summary, targeting GSK-3β effectively inhibits CD4<sup>+</sup> T lymphocyte activation and cytokine production. |
| first_indexed | 2024-03-10T19:18:26Z |
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| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T19:18:26Z |
| publishDate | 2020-06-01 |
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| spelling | doaj.art-ed12507cedfb4a0595b4dc8a2a8876172023-11-20T03:13:27ZengMDPI AGCells2073-44092020-06-0196142410.3390/cells9061424Glycogen Synthase Kinase-3β Facilitates Cytokine Production in 12-O-Tetradecanoylphorbol-13-Acetate/Ionomycin-Activated Human CD4<sup>+</sup> T LymphocytesCheng-Chieh Tsai0Chin-Kun Tsai1Po-Chun Tseng2Chiou-Feng Lin3Chia-Ling Chen4Department of Nursing, Chung Hwa University of Medical Technology, Tainan 703, TaiwanDepartment of Microbiology and Immunology, National Cheng Kung University, Tainan 701, TaiwanDepartment of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, TaiwanDepartment of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, TaiwanSchool of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei 110, TaiwanCytokines are the major immune regulators secreted from activated CD4<sup>+</sup> T lymphocytes that activate adaptive immunity to eradicate nonself cells, including pathogens, tumors, and allografts. The regulation of glycogen synthase kinase (GSK)-3β, a serine/threonine kinase, controls cytokine production by regulating transcription factors. The artificial in vitro activation of CD4<sup>+</sup> T lymphocytes by a combination of 12-O-tetradecanoylphorbol-13-acetate and ionomycin, the so-called T/I model, led to an inducible production of cytokines, such as interferon-γ, tumor necrosis factor-α, and interleukin-2. As demonstrated by the approaches of pharmacological targeting and genetic knockdown of GSK-3β, T/I treatment effectively caused GSK-3β activation followed by GSK-3β-regulated cytokine production. In contrast, pharmacological inhibition of the proline-rich tyrosine kinase 2 and calcineurin signaling pathways blocked cytokine production, probably by deactivating GSK-3β. The blockade of GSK-3β led to the inhibition of the nuclear translocation of T-bet, a vital transcription factor of T lymphocyte cytokines. In a mouse model, treatment with the GSK-3β inhibitor 6-bromoindirubin-3’-oxime significantly inhibited T/I-induced mortality and serum cytokine levels. In summary, targeting GSK-3β effectively inhibits CD4<sup>+</sup> T lymphocyte activation and cytokine production.https://www.mdpi.com/2073-4409/9/6/1424glycogen synthase kinase-3cytokine12-O-tetradecanoylphorbol-13-acetate/ionomycinCD4<sup>+</sup> T lymphocyte |
| spellingShingle | Cheng-Chieh Tsai Chin-Kun Tsai Po-Chun Tseng Chiou-Feng Lin Chia-Ling Chen Glycogen Synthase Kinase-3β Facilitates Cytokine Production in 12-O-Tetradecanoylphorbol-13-Acetate/Ionomycin-Activated Human CD4<sup>+</sup> T Lymphocytes Cells glycogen synthase kinase-3 cytokine 12-O-tetradecanoylphorbol-13-acetate/ionomycin CD4<sup>+</sup> T lymphocyte |
| title | Glycogen Synthase Kinase-3β Facilitates Cytokine Production in 12-O-Tetradecanoylphorbol-13-Acetate/Ionomycin-Activated Human CD4<sup>+</sup> T Lymphocytes |
| title_full | Glycogen Synthase Kinase-3β Facilitates Cytokine Production in 12-O-Tetradecanoylphorbol-13-Acetate/Ionomycin-Activated Human CD4<sup>+</sup> T Lymphocytes |
| title_fullStr | Glycogen Synthase Kinase-3β Facilitates Cytokine Production in 12-O-Tetradecanoylphorbol-13-Acetate/Ionomycin-Activated Human CD4<sup>+</sup> T Lymphocytes |
| title_full_unstemmed | Glycogen Synthase Kinase-3β Facilitates Cytokine Production in 12-O-Tetradecanoylphorbol-13-Acetate/Ionomycin-Activated Human CD4<sup>+</sup> T Lymphocytes |
| title_short | Glycogen Synthase Kinase-3β Facilitates Cytokine Production in 12-O-Tetradecanoylphorbol-13-Acetate/Ionomycin-Activated Human CD4<sup>+</sup> T Lymphocytes |
| title_sort | glycogen synthase kinase 3β facilitates cytokine production in 12 o tetradecanoylphorbol 13 acetate ionomycin activated human cd4 sup sup t lymphocytes |
| topic | glycogen synthase kinase-3 cytokine 12-O-tetradecanoylphorbol-13-acetate/ionomycin CD4<sup>+</sup> T lymphocyte |
| url | https://www.mdpi.com/2073-4409/9/6/1424 |
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