1,25-dihydroxyvitamin-D3 promotes neutrophil apoptosis in periodontitis with type 2 diabetes mellitus patients via the p38/MAPK pathway

Tang, Yaping; Liu, Junyu; Yan, Yanmei; Fang, Hui; Guo, Chengwei; Xie, Rui-Di; Liu, Qi

doi:10.1097/md.0000000000013903

Cited by 20 publications

(13 citation statements)

References 63 publications

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“…Vitamin D can regulate a variety of important pathways [34][35][36][37] . Among these, the NF-κB pathway plays an important role in the regulation of cisplatin sensitivity.…”

Section: Discussionmentioning

confidence: 99%

Vitamin D promotes the cisplatin sensitivity of oral squamous cell carcinoma by inhibiting LCN2-modulated NF-κB pathway activation through RPS3

Huang

Zhang

et al. 2019

Cell Death Dis

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Chemoresistance is a major cause of cancer progression and the mortality of cancer patients. Developing a safe strategy for enhancing chemosensitivity is a challenge for biomedical science. Recent studies have suggested that vitamin D supplementation may decrease the risk of many cancers. However, the role of vitamin D in chemotherapy remains unknown. We found that vitamin D sensitised oral cancer cells to cisplatin and partially reversed cisplatin resistance. Using RNA-seq, we discovered that lipocalin 2 (LCN2) is an important mediator. Cisplatin enhanced the expression of LCN2 by decreasing methylation at the promoter, whereas vitamin D enhanced methylation and thereby inhibited the expression of LCN2. Overexpression of LCN2 increased cell survival and cisplatin resistance both in vitro and in vivo. High LCN2 expression was positively associated with differentiation, lymph node metastasis, and T staging and predicted a poor prognosis in oral squamous cell carcinoma (OSCC) patients. LCN2 was also associated with post-chemotherapy recurrence. Moreover, we found that LCN2 promoted the activation of NF-κB by binding to ribosomal protein S3 (RPS3) and enhanced the interaction between RPS3 and p65. Our study reveals that vitamin D can enhance cisplatin chemotherapy and suggests that vitamin D should be supplied during chemotherapy; however, more follow-up clinical studies are needed.

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“…Vitamin D can regulate a variety of important pathways [34][35][36][37] . Among these, the NF-κB pathway plays an important role in the regulation of cisplatin sensitivity.…”

Section: Discussionmentioning

confidence: 99%

Vitamin D promotes the cisplatin sensitivity of oral squamous cell carcinoma by inhibiting LCN2-modulated NF-κB pathway activation through RPS3

Huang

Zhang

et al. 2019

Cell Death Dis

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“…Mcl‐1 is an anti‐apoptotic Bcl‐2 family protein that is a key regulator of neutrophil survival. Activators of p38 MAPK signalling, such as vitamin D, have been shown to have a pro‐apoptotic effect on neutrophils via regulation of expression of Bcl‐2 and caspase family member genes [36,37]. While we saw changes in the levels of Mcl‐1, caspase‐8 and caspase‐9 protein in our experiments, we did not see any change in expression of these genes in our RNA‐seq experiment (data not shown), indicating that the effects of IFN‐α regulating Mcl‐1 dependent apoptosis are probably via post‐translational modifications.…”

Section: Discussionmentioning

confidence: 58%

Type I interferon regulates cytokine-delayed neutrophil apoptosis, reactive oxygen species production and chemokine expression

Glennon‐Alty

Moots

Edwards

et al. 2020

Clinical &Amp; Experimental Immunology

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Summary Interferons (IFNs) are key regulators of a number of inflammatory conditions in which neutrophils play an important role in pathology, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), where type I IFNs are implicated in disease pathology. However, IFNs are usually generated in vivo together with other cytokines that also have immunoregulatory functions, but such interactions are poorly defined experimentally. We measured the effects of type I (IFN-α) IFN, elevated in both RA and SLE, on the functions of healthy neutrophils incubated in vitro in the absence and presence of proinflammatory cytokines typically elevated in inflammatory diseases [tumour necrosis factor (TNF-α), granulocyte–macrophage colony-stimulating factor (GM-CSF)]. IFN-α alone had no effect on neutrophil apoptosis; however, it abrogated the anti-apoptotic effect of GM-CSF (18 h, P < 0·01). The enhanced stability of the anti-apoptotic protein myeloid cell leukaemia 1 (Mcl-1) and delayed activation of caspase activation normally regulated by GM-CSF were blocked by IFN-α: this effect was mediated, in part, by activation of p38 mitogen-activated protein kinase (MAPK). IFN-α alone also primed reactive oxygen species (ROS) production and maintained the transient priming effect of TNF-α for up to 4 h: it also down-regulated GM-CSF- and TNF-α-activated expression of chemokine (C-X-C motif) ligand (CXCL)1, CXCL2, CXCL3, CXCL8, CCL3 and CCL4 but, in contrast, increased the expression of CXCL10. These novel data identify complex regulatory signalling networks in which type I IFNs profoundly alter the response of neutrophils to inflammatory cytokines. This is likely to have important consequences in vivo and may explain the complexity and heterogeneity of inflammatory diseases such as RA, in which multiple cytokine cascades have been activated.

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“…Activators of p38 MAPK signalling, such as vitamin D, have been shown to have a pro-apoptotic effect on neutrophils via regulation of expression of Bcl-2 and caspase family member genes (Tang et al, 2018;Yang et al, 2015). Whilst we saw changes in the levels of Mcl-1, caspase-8 and caspase-9 protein in our experiments, we did not see any change in expression of these genes in our RNAseq experiment (data not shown), suggesting the effect of IFNα is post-translational.…”

Section: Discussionmentioning

confidence: 99%

Type I Interferon regulates cytokine-delayed neutrophil apoptosis, reactive oxygen species production and chemokine expression via activation of p38 MAPK

Glennon‐Alty

Moots

Edwards

et al. 2020

Preprint

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ABSTRACTInterferons (IFNs) are key regulators of a number of inflammatory conditions in which neutrophils play an important role in pathology, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), where Type I IFNs are implicated in disease pathology. However, IFNs are usually generated in vivo together with other cytokines that also have immunoregulatory functions but such interactions are poorly-defined experimentally. We measured the effects of Type-I IFN (IFNα), elevated in both RA and SLE, on the functions of healthy neutrophils incubated in vitro in the absence and presence of pro-inflammatory cytokines typically elevated in inflammatory diseases (TNFα, GM-CSF). IFNα alone had no effect on neutrophil apoptosis, however it did abrogate the anti-apoptotic effect of GM-CSF (18h, p< 0.01). The enhanced stabilty of the anti-apoptotic protein Mcl-1 and delayed activation of caspase activation normally regulated by GM-CSF were blocked by IFNα: this effect was mediated, in part, by activation of p38 MAPK, increased turnover of the anti-apoptotic protein Mcl-1 and cleavage of caspases. IFNα alone also primed ROS production alone and maintained the transient priming effect of TNF for up to 4h: it also down-regulated GM-CSF and TNFα-activated expression of CXCL1, CXCL2, CXCL3, CXCL8, CCL3 and CCL4, but in contrast increased the expression of CXCL10. These novel data identify complex regulatory signalling networks in which Type I IFNs profoundly alter the response of neutrophils to inflammatory cytokines. This is likely to have important consequences in vivo and may explain the complexity and heterogeneity of inflammatory diseases such as RA, in which multiple cytokine cascades have been activated.

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1,25-dihydroxyvitamin-D3 promotes neutrophil apoptosis in periodontitis with type 2 diabetes mellitus patients via the p38/MAPK pathway

Cited by 20 publications

References 63 publications

Vitamin D promotes the cisplatin sensitivity of oral squamous cell carcinoma by inhibiting LCN2-modulated NF-κB pathway activation through RPS3

Vitamin D promotes the cisplatin sensitivity of oral squamous cell carcinoma by inhibiting LCN2-modulated NF-κB pathway activation through RPS3

Type I interferon regulates cytokine-delayed neutrophil apoptosis, reactive oxygen species production and chemokine expression

Type I Interferon regulates cytokine-delayed neutrophil apoptosis, reactive oxygen species production and chemokine expression via activation of p38 MAPK

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