Interleukin-4 activates divergent cell-intrinsic signals to regulate retinal cell proliferation induced by classical growth factors

Silva, Gustavo Mataruna da; Figueiredo, Camila Saggioro de; Oliveira, Amanda Cândida da Rocha; Raony, Ícaro; Miranda, Raphael Amorim de Araújo; Silva, Eliezer de Mello; Guilarducci, Carla Valéria Vieira; Santos, Aline Araújo dos; Giestal-de-Araujo, Elizabeth

doi:10.1016/j.mcn.2022.103780

Cited by 2 publications

(1 citation statement)

References 79 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A possible explanation for the increase in IL-4 and IL-13 in our experiments is that both cytokines are associated with p53 signaling. IL-13 has been shown to reduce p53 signaling and expression of caspase-3 in activated T cells [49], while IL-4 has been associated with both suppression and activation of p53 signaling [50,51]. We speculate that the increased production of IL-4 and IL-13 in LMS-treated T cells could possibly be part of a feedback mechanism that dampens p53 signaling, which is in line with the modest p53 activation in LMS-treated T cells.…”

Section: Discussionmentioning

confidence: 59%

Levamisole suppresses activation and proliferation of human T cells by the induction of a p53‐dependent DNA damage response

Khan,

Veltkamp,

Scheper

et al. 2023

Eur J Immunol

View full text Add to dashboard Cite

Levamisole (LMS) is a small molecule used in the treatment of idiopathic nephrotic syndrome (INS). The pathogenesis of INS remains unknown, but evidence points towards 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 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.This article is protected by copyright. All rights reserved

show abstract

Section: Discussionmentioning

confidence: 59%

Levamisole suppresses activation and proliferation of human T cells by the induction of a p53‐dependent DNA damage response

Khan,

Veltkamp,

Scheper

et al. 2023

Eur J Immunol

View full text Add to dashboard Cite

show abstract

Levamisole suppresses activation and proliferation of human T cells by the induction of a p53-dependent DNA damage response

Khan

Veltkamp

Scheper

et al. 2023

Preprint

View full text Add to dashboard Cite

Levamisole (LMS) is a small molecule used in the treatment of idiopathic nephrotic syndrome (INS). The pathogenesis of INS remains unknown, but most evidence points towards an immunological basis of the disease. Recently, LMS has been shown to increase the relapse-free survival in INS patients treated in combination with corticosteroids with relatively few side effects. While LMS has been hypothesized to exert an immunomodulatory effect, its mechanism of action remains unknown. To provide insight into the working mechanism of LMS, we studied its immunomodulatory activity on in vitro activated human T cells. We show here that treatment with LMS decreased activation and proliferation of human CD4+ and CD8+ T cells. In addition, production of T cell activation-associated cytokines such as IL-2, TNF-alpha and IFN-gamma were reduced upon LMS treatment, whereas IL-4 and IL-13 production was increased. Gene expression profiling confirmed the suppressive effects of LMS on proliferation as numerous genes involved in cell cycle progression were downregulated. Furthermore, genes associated with p53 activation and cell cycle arrest 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. Cell cycle analysis showed that LMS induced a mid-S phase arrest indicating the activation of a replication stress-associated checkpoint. In support, LMS treatment resulted in gamma H2AX-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.

show abstract

Interleukin-4 activates divergent cell-intrinsic signals to regulate retinal cell proliferation induced by classical growth factors

Cited by 2 publications

References 79 publications

Levamisole suppresses activation and proliferation of human T cells by the induction of a p53‐dependent DNA damage response

Levamisole suppresses activation and proliferation of human T cells by the induction of a p53‐dependent DNA damage response

Levamisole suppresses activation and proliferation of human T cells by the induction of a p53-dependent DNA damage response

Contact Info

Product

Resources

About