Regulation of macrophage activation and septic shock susceptibility <i>via</i> p21(WAF1/CIP1)

Trakala, Marianna; Arias, Cristina Fernández; García, María Isabel Ávalos; Moreno-Ortiz, M. Carmen; Tsilingiri, Katerina; Fernández, Pablo J.; Mellado, Mario; Diaz‐Meco, María T.; Moscat, Jorge; Serrano, Manuel; Martı́nez-A, Carlos; Balomenos, Dimitrios

doi:10.1002/eji.200838676

Cited by 65 publications

(75 citation statements)

References 39 publications

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“…Waf1 is a negative regulator that curbs excessive macrophage activation by providing a negative feedback system of TNF-a and IL-1b production (38,39). We propose a similar function for Trex1 as macrophage controller of activation.…”

Section: Discussionmentioning

confidence: 92%

The Exonuclease Trex1 Restrains Macrophage Proinflammatory Activation

Pereira-Lopes

Celhar

Sans-Fons

et al. 2013

The Journal of Immunology

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The three-prime repair exonuclease 1 (TREX1) is the most abundant exonuclease in mammalian cells. Mutations in Trex1 gene are being linked to the development of Aicardi–Goutières syndrome, an inflammatory disease of the brain, and systemic lupus erythematosus. In clinical cases and in a Trex1-deficient murine model, chronic production of type I IFN plays a pathogenic role. In this study, we demonstrate that Trex1−/− mice present inflammatory signatures in many different organs, including the brain. Trex1 is highly induced in macrophages in response to proinflammatory stimuli, including TLR7 and TLR9 ligands. Our findings show that, in the absence of Trex1, macrophages displayed an exacerbate proinflammatory response. More specifically, following proinflammatory stimulation, Trex1−/− macrophages exhibited an increased TNF-α and IFN-α production, higher levels of CD86, and increased Ag presentation to CD4+ T cells, as well as an impaired apoptotic T cell clearance. These results evidence an unrevealed function of the Trex1 as a negative regulator of macrophage inflammatory activation and demonstrate that macrophages play a major role in diseases associated with Trex1 mutations, which contributes to the understanding of inflammatory signature in these diseases.

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Section: Discussionmentioning

confidence: 92%

The Exonuclease Trex1 Restrains Macrophage Proinflammatory Activation

Pereira-Lopes

Celhar

Sans-Fons

et al. 2013

The Journal of Immunology

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“…Importantly, p53 and p21 are reported to be antiinflammation factors (27)(28)(29). Furthermore, p21 is a negative regulator of macrophage activation; in particular, it inhibits the lipopolysaccharide-dependent stimulation of TNF-α and IL-1β (29,30). Moreover, the inhibition caused by p21 inhibits the NF-κB activity (29,30).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, p21 is a negative regulator of macrophage activation; in particular, it inhibits the lipopolysaccharide-dependent stimulation of TNF-α and IL-1β (29,30). Moreover, the inhibition caused by p21 inhibits the NF-κB activity (29,30). Yanaka et al (7) reported the inhibitory effect of PL on the lipopolysaccharide-dependent activation of NF-κB in macrophages.…”

Section: Discussionmentioning

confidence: 99%

Vitamin B6 activates p53 and elevates p21 gene expression in cancer cells and the mouse colon

et al. 2014

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Abstract. Increasing evidence indicates vitamin B 6 acts as a protective factor against colon cancer. However, the mechanisms of the effect of vitamin B 6 are poorly understood. The present preliminary study using DNA microarray and realtime PCR indicates p21 mRNA is upregulated in human colon carcinoma (HT29) cells exposed to pyridoxal (PL, 500 µM). A similar effect was observed in human epithelial colorectal adenocarcinoma (Caco2) cells, human colon adenocarcinoma (LoVo) cells, human embryonic kidney (HEK293T) cells, and human hepatoma (HepG2) cells. Adding other B 6 -vitamers such as pyridoxal 5'-phosphate (PLP), pyridoxine (PN), and pyridoxamine (PM) caused no such effect. In order to understand the mechanism of higher mRNA expression of p21 by PL, effect of PL on the p53 activation was examined (the upstream factor for p21 mRNA transcription) in HT29 cells, LoVo cells, and HepG2 cells. PL increased the phosphorylated p53 protein levels (active form) in whole-cell lysates and the nuclei of the cells. Noteworthy, the consumption of a vitamin B 6 -deficient diet for 5 weeks significantly reduced p21 mRNA levels and tended to reduce phosphorylated p53 protein levels (P=0.053) in the colons of mice compared to a diet with adequate vitamin B 6 . Thus, these results suggest vitamin B 6 plays a role in increasing p21 gene expression via p53 activation in several cancer cells and the mouse colon.

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“…Elevated NF-κB activity and secretion of cytokines was also found in LPSstimulated p21-deficient mouse and human macrophages as compared to similarly treated wild-type cells. 82,83 It will be interesting to learn whether the increased inflammatory status of p21-/-mice is p53 dependent.…”

Section: P53 As An Inhibitor Of Inflammationmentioning

confidence: 99%

Inflammation and p53: A Tale of Two Stresses

Gudkov

Gurova²,

Komarova³

2011

Genes & Cancer

177

145

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Numerous observations indicate a strong link between chronic inflammation and cancer. This link is supported by substantial experimental evidence indicating mutual negative regulation of NF-κB, the major regulator of inflammation, and p53, the major tumor suppressor. This antagonistic relationship reflects the opposite principles of the physiological responses driven by these transcription factors, which act as sensors and mediators of intrinsic and extrinsic cell stresses, respectively. Constitutive activation of NF-κB, the underlying cause of chronic inflammation, is a common acquired characteristic of tumors. A variety of experimental methods have been used to demonstrate that constitutive activation of NF-κB reduces the tumor suppressor activity of p53, thereby creating permissive conditions for dominant oncogene-mediated transformation. Loss of p53 activity is also a characteristic of the majority of tumors and results in unleashed inflammatory responses due to loss of p53-mediated NF-κB suppression. On the other hand, in natural or pharmacological situations of enforced p53 activation, NF-κB activity, inflammation, and immune responses are reduced, resulting in different pathologies. It is likely that the chronic inflammation that is commonly acquired in various tissues of older mammals leads to general suppression of p53 function, which would explain the increased risk of cancer observed in aging animals and humans. Although the molecular mechanisms underlying reciprocal negative regulation of p53 and NF-κB remain to be deciphered, this phenomenon has important implications for pharmacological prevention of cancer and aging and for new approaches to control inflammation.

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Regulation of macrophage activation and septic shock susceptibility via p21(WAF1/CIP1)

Cited by 65 publications

References 39 publications

The Exonuclease Trex1 Restrains Macrophage Proinflammatory Activation

The Exonuclease Trex1 Restrains Macrophage Proinflammatory Activation

Vitamin B6 activates p53 and elevates p21 gene expression in cancer cells and the mouse colon

Inflammation and p53: A Tale of Two Stresses

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