TY - JOUR
T1 - Levamisole suppresses activation and proliferation of human T cells by the induction of a p53-dependent DNA damage response
AU - Khan, Gerarda H.
AU - Veltkamp, Floor
AU - Scheper, Mirte
AU - Hoebe, Ron A.
AU - Claessen, Nike
AU - Butter, Loes
AU - Bouts, Antonia H. M.
AU - Florquin, Sandrine
AU - Guikema, Jeroen E. J.
N1 - Funding Information: The authors would like to thank Berend Hooibrink, Kim Brandwijk‐Paarlberg, and Toni van Capel for their excellent flow cytometry support. The authors would also like to thank Dr. Alessandra Tammaro for providing extensive theoretical and technical input. This work was funded by the Dutch Kidney Foundation (DKF, CP 16.03). Publisher Copyright: © 2023 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.
PY - 2023/11
Y1 - 2023/11
N2 - Levamisole (LMS) is a small molecule used in the treatment of idiopathic nephrotic syndrome (INS). The pathogenesis of INS remains unknown, but evidence points toward an immunological basis of the disease. Recently, LMS has been shown to increase the relapse-free survival in INS patients. While LMS has been hypothesized to exert an immunomodulatory effect, its mechanism of action remains unknown. Here, we show that LMS decreased activation and proliferation of human T cells. T-cell activation-associated cytokines such as IL-2, TNF-α, and IFN-γ were reduced upon LMS treatment, whereas IL-4 and IL-13 were increased. Gene expression profiling confirmed that the suppressive effects of LMS as genes involved in cell cycle progression were downregulated. Furthermore, genes associated with p53 activation were upregulated by LMS. In agreement, LMS treatment resulted in p53 phosphorylation and increased expression of the p53 target gene FAS. Accordingly, LMS sensitized activated T cells for Fas-mediated apoptosis. LMS treatment resulted in a mid-S phase cell cycle arrest accompanied by γH2AX-foci formation and phosphorylation of CHK1. Our findings indicate that LMS acts as an immunosuppressive drug that directly affects the activation and proliferation of human T cells by induction of DNA damage and the activation of a p53-dependent DNA damage response.
AB - Levamisole (LMS) is a small molecule used in the treatment of idiopathic nephrotic syndrome (INS). The pathogenesis of INS remains unknown, but evidence points toward an immunological basis of the disease. Recently, LMS has been shown to increase the relapse-free survival in INS patients. While LMS has been hypothesized to exert an immunomodulatory effect, its mechanism of action remains unknown. Here, we show that LMS decreased activation and proliferation of human T cells. T-cell activation-associated cytokines such as IL-2, TNF-α, and IFN-γ were reduced upon LMS treatment, whereas IL-4 and IL-13 were increased. Gene expression profiling confirmed that the suppressive effects of LMS as genes involved in cell cycle progression were downregulated. Furthermore, genes associated with p53 activation were upregulated by LMS. In agreement, LMS treatment resulted in p53 phosphorylation and increased expression of the p53 target gene FAS. Accordingly, LMS sensitized activated T cells for Fas-mediated apoptosis. LMS treatment resulted in a mid-S phase cell cycle arrest accompanied by γH2AX-foci formation and phosphorylation of CHK1. Our findings indicate that LMS acts as an immunosuppressive drug that directly affects the activation and proliferation of human T cells by induction of DNA damage and the activation of a p53-dependent DNA damage response.
KW - DNA damage
KW - Idiopathic nephrotic syndrome
KW - Levamisole
KW - Proliferation
KW - T cells
UR - http://www.scopus.com/inward/record.url?scp=85169311466&partnerID=8YFLogxK
U2 - https://doi.org/10.1002/eji.202350562
DO - https://doi.org/10.1002/eji.202350562
M3 - Article
C2 - 37597325
SN - 0014-2980
VL - 53
JO - European journal of immunology
JF - European journal of immunology
IS - 11
M1 - 2350562
ER -