Lipopolysaccharide downregulates the expression of p53 through activation of MDM2 and enhances activation of nuclear factor-kappa B

Odkhuu, Erdenezaya; Mendjargal, Adilsaikhan; Koide, Naoki; Naiki, Yoshikazu; Komatsu, Takayuki; Yokochi, Takashi

doi:10.1016/j.imbio.2014.08.010

Cited by 18 publications

(15 citation statements)

References 30 publications

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“…For instance, nutlin-3-triggered p53 activity promotes the production of pro-inflammatory cytokines in human macrophages, including TNF-α, IL-6, and IL-8, via cooperation with the NF-κB pathway [39]. Other reports indicated a contrary phenomenon in which macrophages from p53 -/-mice produced increased pro-inflammatory cytokines in response to LPS [40]. Furthermore, p53 plays an essential role in promoting M2 macrophage polarization, which expresses anti-inflammatory cytokines [41].…”

Section: Discussionmentioning

confidence: 99%

Novel Role of p53 in Septic Immunosuppression: Involvement in Loss and Dysfunction of CD4+ T Lymphocytes

Zhang

Ren

et al. 2018

Cell Physiol Biochem

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Background/Aims: Immunosuppression frequently occurs during the development of sepsis and is closely associated with poor outcome. Characteristics of immunosuppressive CD4⁺ T lymphocytes in sepsis have been reported to include dramatic cell loss and inactivation. p53 acts as a pivotal transcription factor in regulating cell proliferation and apoptosis, which control tumorigenesis. However, few studies have investigated the universal role of p53 in immune cells, especially in the development of sepsis. Methods: A mouse model of sepsis was produced by cecal ligation and puncture (CLP), and isolated splenic CD4⁺ T cells or Jurkat cells were exposed to lipopolysaccharide (LPS) stimulation in vitro. We used genetic knockout (p53^-/-) mice or the specific inhibitor pifithrin-α (PFT) to investigate the regulatory mechanisms of p53. Cell proliferation ability was assessed using a Cell Counting Kit-8 assay, and apoptotic cells were stained with annexin V/propidium iodide and then analyzed using a FACScan flow cytometer. Protein and mRNA expression levels were measured by western blotting and real-time PCR, and cytokine levels in culture supernatants were determined by enzyme-linked immunosorbent assay. Results: Splenic CD4⁺ T lymphocytes from CLP mice expressed gradually elevated p53 mRNA and protein levels, which resulted in extracellular regulated protein kinase 1/2 inactivation and expression of apoptotic molecules. Specific inhibition of p53 by PFT or genetic knockout (p53^-/-) maintained CD4⁺ T lymphocyte homeostasis, as indicated by protection from cell loss and restoration of immune function. A medium dose of PFT improved the survival rate of mice, while mortality rate showed only a slight improvement in p53^-/- mice compared with wild-type mice. The in vitro responses to LPS were consistent with these results, and upregulation of p53 clearly affected the proliferation, apoptosis, and immune dysfunction of CD4⁺ T lymphocytes. In addition, we confirmed the regulatory effect of p53 in Jurkat cells, and inhibition of p53 by either inhibition or short hairpin RNA transduction markedly protected cells from LPS stimulation. Conclusion: Elevation of p53 in T lymphocytes during sepsis or endotoxin challenge might be responsible for inhibiting cell proliferation and enhancing both apoptosis and immune dysfunction of T cells.

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Section: Discussionmentioning

confidence: 99%

Novel Role of p53 in Septic Immunosuppression: Involvement in Loss and Dysfunction of CD4+ T Lymphocytes

Zhang

Ren

et al. 2018

Cell Physiol Biochem

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“…NFkB is activated after exposure to a variety of stimuli, such as oxidative stressors or pathogens, and induces the expression of genes involved in the innate immune response [4]. For example, systemic treatment with lipopolysaccharide (LPS), a bacterial endotoxin, leads to significant increases in NFkB activity and proinflammatory cytokine production [5]. NFkB activation and subsequent cytokine production have also been shown to influence depressive-like behaviors, specifically social avoidance and anhedonia [6][7][8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Cellular and behavioral effects of lipopolysaccharide treatment are dependent upon neurokinin-1 receptor activation

Fulenwider

Smith

Nichenko

et al. 2018

J Neuroinflammation

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Background: Several psychiatric conditions are affected by neuroinflammation and neuroimmune activation. The transcription factor nuclear factor kappa light-chain-enhancer of activated B cells (NFkB) plays a major role in inflammation and innate immunity. The neurokinin-1 receptor (NK1R) is the primary endogenous target of the neuroactive peptide substance P, and some data suggests that NK1R stimulation may influence NFkB activity. Both NK1R and NFkB have been shown to play a functional role in complex behaviors including stress responsivity, depression, and addiction. In this study, we test whether NFkB activity in the brain (stimulated by lipopolysaccharide administration) is dependent upon the NK1R. Methods: Adult male Wistar rats were treated systemically with the NK1R antagonist L822429 followed by administration of systemic lipopolysaccharide (LPS, a strong activator of NFkB). Hippocampal extracts were used to assess expression of proinflammatory cytokines and NFkB-DNA-binding potential. For behavioral studies, rats were trained to consume 1% (w/v) sucrose solution in a continuous access two-bottle choice model. After establishment of baseline, animals were treated with L822429 and LPS and sucrose preference was measured 12 h post-treatment. Results: Systemic LPS treatment causes a significant increase in proinflammatory cytokine expression and NFkB-DNA-binding activity within the hippocampus. These increases are attenuated by systemic pretreatment with the NK1R antagonist L822429. Systemic LPS treatment also led to the development of anhedonic-like behavior, evidenced by decreased sucrose intake in the sucrose preference test. This behavior was significantly attenuated by systemic pretreatment with the NK1R antagonist L822429. Conclusions: Systemic LPS treatment induced significant increases in NFkB activity, evidenced by increased NFkB-DNA binding and by increased proinflammatory cytokine expression in the hippocampus. LPS also induced anhedonic-like behavior. Both the molecular and behavioral effects of LPS treatment were significantly attenuated by systemic NK1R antagonism, suggesting that NK1R stimulation lies upstream of NFkB activation following systemic LPS administration and is at least in part responsible for NFkB activation.

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“…35 To interpret the putative role of NFjB in modulating the p53 expression, we simulated the in vivo conditions in vitro. The dose of LPS used in the in vitro studies was in accordance with that of a previously described method, 36 which indicates that culturing Raw 264.7 macrophage cells in the presence of 0.1 lg mL À1 showed noticeable downregulation of p53 expression through significant activation of NFjB and Mdm2 after 24 h of incubation. 36 Therefore, in this study, we cultured thymocytes in the presence of LPS (0.1 lg mL À1 ) for 24 h and found similar results as explained by Odkhuua et al, 36 as evidenced by significant decrease in the p53 nuclear expression along with increase in NFjB nuclear expression.…”

Section: Discussionmentioning

confidence: 94%

Fluoxetine triggers selective apoptosis in inflammation‐induced proliferating (Ki‐67^high) thymocytes

et al. 2019

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Inappropriate functioning of the immune system is observed during sustained systemic inflammation, which might lead to immune deficiencies, autoimmune disorders and cancer. Primary lymphoid organs may progress to a deregulated proliferative state in response to inflammatory signals in order to intensify host defense mechanisms and exacerbate an inflammatory niche. Fluoxetine, a selective serotonin reuptake inhibitor, has recently been projected as an anti‐inflammatory agent. This study had been designed to evaluate the potential novel role of fluoxetine in reversing inflammation‐induced immune dysfunction. Lipopolysaccharide (LPS) administration in Swiss albino mice potentiated a systemic inflammatory response, along with increased proliferation of thymocytes and peripheral blood mononuclear cells, as evident from increased Ki‐67 expression. The proliferative changes in the immune system were mainly associated with increased phosphorylation of PI3k, AKT and IκB along with elevated NFκB‐p65 nuclear translocation. The Ki‐67high thymocytes obtained from LPS administered mice demonstrated significantly low p53 nuclear activity, which was established to be mediated by NFκB through reduced nuclear translocation of p53 during LPS‐induced proliferative conditions, thereby blocking p53‐dependent apoptosis. Fluoxetine supplementation not only reversed the proinflammatory condition, but also induced selective apoptosis in the proliferation‐dictated Ki‐67high thymocytes possibly by modulating the hypothalamus–pituitary–adrenal axis and inducing glucocorticoid receptor activation and apoptosis in these proliferation‐biased immune cells, authenticating a novel antiproliferative role of an established drug.

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Lipopolysaccharide downregulates the expression of p53 through activation of MDM2 and enhances activation of nuclear factor-kappa B

Cited by 18 publications

References 30 publications

Novel Role of p53 in Septic Immunosuppression: Involvement in Loss and Dysfunction of CD4+ T Lymphocytes

Novel Role of p53 in Septic Immunosuppression: Involvement in Loss and Dysfunction of CD4+ T Lymphocytes

Cellular and behavioral effects of lipopolysaccharide treatment are dependent upon neurokinin-1 receptor activation

Fluoxetine triggers selective apoptosis in inflammation‐induced proliferating (Ki‐67^high) thymocytes

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Lipopolysaccharide downregulates the expression of p53 through activation of MDM2 and enhances activation of nuclear factor-kappa B

Cited by 18 publications

References 30 publications

Novel Role of p53 in Septic Immunosuppression: Involvement in Loss and Dysfunction of CD4+ T Lymphocytes

Novel Role of p53 in Septic Immunosuppression: Involvement in Loss and Dysfunction of CD4+ T Lymphocytes

Cellular and behavioral effects of lipopolysaccharide treatment are dependent upon neurokinin-1 receptor activation

Fluoxetine triggers selective apoptosis in inflammation‐induced proliferating (Ki‐67high) thymocytes

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Fluoxetine triggers selective apoptosis in inflammation‐induced proliferating (Ki‐67^high) thymocytes