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Cited by 54T-cell and B-cell ImmunologyPsoriasis: Treatment and PathogenesisTGF-β signaling in diseases

Inhibition of Cdk8/Cdk19 Activity Promotes Treg Cell Differentiation and Suppresses Autoimmune Diseases

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Guo, Zengli, Wang, Gang, Lv, Yanfang, Wan, Yisong Y., Zheng, Junnian·2019·Frontiers in Immunology
DOI 10.3389/fimmu.2019.01988PMC PMC6736578
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Abstract

Foxp3 expressing regulatory T (Treg) cells, as the central negative regulator of adaptive immune system, are essential to suppress immune response and maintain immune homeostasis. However, the function of Treg cells is frequently compromised in autoimmunity and hyper-activated in infections and tumor microenvironments. Thus, manipulating Treg cells becomes a promising therapeutic strategy for treating various diseases. Here we reported that inhibition of Cdk8/Cdk19 activity by small molecule inhibitors CCT251921 or Senexin A greatly promoted the differentiation of Treg cells and the expression of Treg signature genes, such as Foxp3, CTLA4, PD-1, and GITR. Mechanistically, we found that the augmented Treg cell differentiation was due to sensitized TGF-β signaling by Cdk8/Cdk19 inhibition, which was associated with attenuation of IFN-γ-Stat1 signaling and enhancement of phosphorylated Smad2/3. Importantly, treatment with Cdk8/Cdk19 inhibitor CCT251921 significantly increased Treg population and ameliorated autoimmune symptoms in an experimental autoimmune encephalomyelitis (EAE) model. Taken together, our study reveals a novel role of Cdk8/Cdk19 in Treg cell differentiation and provides a potential target for Treg cell based therapeutics.

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  • Small molecule inhibitors targeting CDK8 promote the differentiation of T regulatory cells and Th-17 cells under their respective polarizing conditions.

    “small molecule inhibitors targeting CDK8 promote the differentiation of T regulatory (reg) cells, and Th-17 cells when T cells were placed under T reg polarizing conditions (Akamatsu et al., 2019; Guo et al., 2019), or Th-17 polarizing conditions (Figure 8) respectively”

    From CDK8 fine-tunes IL-6 transcriptional activities by limiting STAT3 resident time at the gene loci (2020) · cites this paper as Guo et al., 2019

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Research works printed but not linked: 22

  1. [1]Sakaguchi S Yamaguchi T Nomura T Ono M. Regulatory T cells and immune tolerance. Cell. (2008) 133: 775– 87. 10.1016/j.cell.2008.05.009 18510923 · DOI
  2. [2]von Boehmer H Daniel C. Therapeutic opportunities for manipulating T(Reg) cells in autoimmunity and cancer. Nat Rev Drug Discov. (2013) 12: 51– 63. 10.1038/nrd3683 23274471 · DOI
  3. [3]Ramsdell F Ziegler SF. FOXP3 and scurfy: how it all began. Nat Rev Immunol. (2014) 14: 343– 9. 10.1038/nri3650 24722479 · DOI
  4. [4]Li MO Flavell RA. TGF-beta: a master of all T cell trades. Cell. (2008) 134: 392– 404. 10.1016/j.cell.2008.07.025 18692464 PMC3677783 · DOI
  5. [5]Tsai KL Sato S Tomomori-Sato C Conaway RC Conaway JW Asturias FJ. A conserved mediator-CDK8 kinase module association regulates mediator-RNA polymerase II interaction. Nat Struct Mol Biol. (2013) 20: 611– 9. 10.1038/nsmb.2549 23563140 PMC3648612 · DOI · Paper page
  6. [6]Firestein R Bass AJ Kim SY Dunn IF Silver SJ Guney I. CDK8 is a colorectal cancer oncogene that regulates beta-catenin activity. Nature. (2008) 455: 547– 51. 10.1038/nature07179 18794900 PMC2587138 · DOI
  7. [8]Alarcon C Zaromytidou AI Xi Q Gao S Yu J Fujisawa S. Nuclear CDKs drive Smad transcriptional activation and turnover in BMP and TGF-beta pathways. Cell. (2009) 139: 757– 69. 10.1016/j.cell.2009.09.035 19914168 PMC2818353 · DOI · Paper page
  8. [9]Cee VJ Chen DY Lee MR Nicolaou KC. Cortistatin A is a high-affinity ligand of protein kinases ROCK, CDK8, and CDK11. Angew Chem Int Ed Engl. (2009) 48: 8952– 7. 10.1002/anie.200904778 19844931 · DOI
  9. [10]Porter DC Farmaki E Altilia S Schools GP West DK Chen M. Cyclin-dependent kinase 8 mediates chemotherapy-induced tumor-promoting paracrine activities. Proc Natl Acad Sci USA. (2012) 109: 13799– 804. 10.1073/pnas.1206906109 22869755 PMC3427077 · DOI
  10. [11]Mallinger A Schiemann K Rink C Stieber F Calderini M Crumpler S. Discovery of potent, selective, and orally bioavailable small-molecule modulators of the mediator complex-associated kinases CDK8 and CDK19. J Med Chem. (2016) 59: 1078– 101. 10.1021/acs.jmedchem.5b01685 26796641 PMC5362750 · DOI
  11. [12]Czodrowski P Mallinger A Wienke D Esdar C Poschke O Busch M. Structure-based optimization of potent, selective, and orally bioavailable CDK8 inhibitors discovered by high-throughput screening. J Med Chem. (2016) 59: 9337– 49. 10.1021/acs.jmedchem.6b00597 27490956 · DOI · Paper page
  12. [13]Johannessen L Sundberg TB O'Connell DJ Kolde R Berstler J Billings KJ. Small-molecule studies identify CDK8 as a regulator of IL-10 in myeloid cells. Nat Chem Biol. (2017) 13: 1102– 8. 10.1038/nchembio.2458 28805801 PMC5693369 · DOI
  13. [14]Pelish HE Liau BB Nitulescu II Tangpeerachaikul A Poss ZC Da Silva DH. Mediator kinase inhibition further activates super-enhancer-associated genes in AML. Nature. (2015) 526: 273– 6. 10.1038/nature14904 26416749 PMC4641525 · DOI
  14. [15]Zheng SG Gray JD Ohtsuka K Yamagiwa S Horwitz DA. Generation ex vivo of TGF-beta-producing regulatory T cells from CD4+CD25- precursors. J Immunol. (2002) 169: 4183– 9. 10.4049/jimmunol.169.8.4183 12370347 · DOI
  15. [16]Ulloa L Doody J Massague J. Inhibition of transforming growth factor-beta/SMAD signalling by the interferon-gamma/STAT pathway. Nature. (1999) 397: 710– 3. 10.1038/17826 10067896 · DOI
  16. [17]Chang JH Kim YJ Han SH Kang CY. IFN-gamma-STAT1 signal regulates the differentiation of inducible Treg: potential role for ROS-mediated apoptosis. Eur J Immunol. (2009) 39: 1241– 51. 10.1002/eji.200838913 19337996 · DOI
  17. [18]Maldonado RA Soriano MA Perdomo LC Sigrist K Irvine DJ Decker T. Control of T helper cell differentiation through cytokine receptor inclusion in the immunological synapse. J Exp Med. (2009) 206: 877– 92. 10.1084/jem.20082900 19349465 PMC2715121 · DOI
  18. [19]O'Connor RA Anderton SM. Foxp3+ regulatory T cells in the control of experimental CNS autoimmune disease. J Neuroimmunol. (2008) 193: 1– 11. 10.1016/j.jneuroim.2007.11.016 18077005 · DOI
  19. [20]Xu W Wang Z Zhang W Qian K Li H Kong D. Mutated K-ras activates CDK8 to stimulate the epithelial-to-mesenchymal transition in pancreatic cancer in part via the Wnt/beta-catenin signaling pathway. Cancer Lett. (2015) 356: 613– 27. 10.1016/j.canlet.2014.10.008 25305448 · DOI
  20. [21]Xu D Li CF Zhang X Gong Z Chan CH Lee SW. Skp2-macroH2A1-CDK8 axis orchestrates G2/M transition and tumorigenesis. Nat Commun. (2015) 6: 6641. 10.1038/ncomms7641 25818643 PMC4500169 · DOI
  21. [22]Kapoor A Goldberg MS Cumberland LK Ratnakumar K Segura MF Emanuel PO. The histone variant macroH2A suppresses melanoma progression through regulation of CDK8. Nature. (2010) 468: 1105– 9. 10.1038/nature09590 21179167 PMC3057940 · DOI
  22. [23]Di Giovanni C Novellino E Chilin A Lavecchia A Marzaro G. Investigational drugs targeting cyclin-dependent kinases for the treatment of cancer: an update on recent findings (2013-2016). Expert Opin Investig Drugs. (2016) 25: 1215– 30. 10.1080/13543784.2016.1234603 27606939 · DOI

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Sorted by citations

Authors
Guo, Z., Wang, G., Lv, Y., Wan, Y. Y., & Zheng, J.
Affiliations
  • University of North Carolina at Chapel Hill (US)
  • Xuzhou Medical College (CN)
Corresponding author
  • Wan, Yisong Y.
  • Zheng, Junnian
ORCID
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2019-08-20
Volume
10
Pages
1988-1988
ISSN
1664-3224 (ISSN-L)
DOI
10.3389/fimmu.2019.01988
PMC
PMC6736578
OpenAlex
W2966264244
Cited by
54
References
1
Citations by year
2026: 9 · 2025: 8 · 2024: 8 · 2023: 7 · 2022: 6 · 2021: 6 · 2020: 10
FWCI
2.20
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Immunology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Multiple Sclerosis Society
  • National Natural Science Foundation of China (BE2016643, CXTDA2017034, 81871869, 81803080)
  • Government of Jiangsu Province
  • Natural Science Foundation of Jiangsu Province (BE2016643, BK20180990, 81871869)
  • Xuzhou Science and Technology Program (KC16HG234)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
Keywords
Treg differentiation, regulatory T cells, Foxp3, TGF-beta signaling, Smad2/3 phosphorylation, small molecule inhibitors, experimental autoimmune encephalomyelitis, autoimmune disease, CTLA-4, PD-1, GITR
MeSH terms
Animals, Cell Differentiation, Encephalomyelitis, Autoimmune, Experimental, Lymphocyte Activation, Mice, Inbred C57BL, Autoimmunity, Cyclin-Dependent Kinases, T-Lymphocytes, Regulatory, Mice, Cyclin-Dependent Kinase 8

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