Increased nuclear factor-κB and loss of p53 are key mechanisms in ME/CFS

[jace]

http://www.medical-hypotheses.com/article/S0306-9877(12)00358-1/abstract

Gerwyn Morris and Michael Maes unpick the difference between ME and CFS. I'm hoping for sight of the full paper soon.

Abstract

Fukuda’s criteria are adequate to make a distinction between Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS) and chronic fatigue (CF), but ME/CFS patients should be subdivided into those with (termed ME) and without (termed CFS) post exertional malaise [Maes et al. 2012]. ME/CFS is considered to be a neuro-immune disease. ME/CFS is characterized by activated immuno-inflammatory pathways, including increased levels of pro-inflammatory cytokines, nuclear factor κB (NF-κB) and aberrations in mitochondrial functions, including lowered ATP.
These processes may explain typical symptoms of ME/CFS, e.g. fatigue, malaise, hyperalgesia, and neurologic and autonomic symptoms. Here we hypothesize that increased NF-κB together with a loss of p53 are key phenomena in ME/CFS that further explain ME/CFS symptoms, such as fatigue and neurocognitive dysfunction, and explain ME symptoms, such as post-exertional malaise following mental and physical activities. Inactivation of p53 impairs aerobic mitochondrial functions and causes greater dependence on anaerobic glycolysis, elevates lactate levels, reduces mitochondrial density in skeletal muscle and reduces endurance during physical exercise.
Lowered p53 and increased NF-κB are associated with elevated reactive oxygen species. Increased NF-κB induces the production of pro-inflammatory cytokines, which increase glycolysis and further compromise mitochondrial functions. All these factors together may contribute to mitochondrial exhaustion and indicate that the demand for extra ATP upon the commencement of increased activity cannot be met. In conditions of chronic inflammation and oxidative stress, high NF-κB and low p53 may conspire to promote neuron and glial cell survival at a price of severely compromised metabolic brain function. Future research should examine p53 signalling in ME/CFS.

 

[Sherlock]

I remember that p53 is used as a prognostic indicator in certain cancers. Another was ki-67- so without looking, I'd guess that has also been looked at in CFS. mTOR would be another. What is wanted to be low in cancer is wanted to be high in CFS.

 

[Mula]

I have not found a p53 paper for MECFS. Do you have one?

 

[alex3619]

Hi Mula, here are three that mention p53. One of these, the last one, is in a table though - easier to find with a search. However, they did say that the p53 pathway is one of a number that is predictive of ME severity.

http://www.hirou.jp/english/pdf/ikuta.pdf

http://db.wdc-jp.com/cgi-bin/psj/data/bpb/pdf/201103/b03_0354.pdf

http://www.bioinformation.net/006/97320630006120.pdf

None of these papers are specifically about p53 however, the discussion arises with respect to other factors.

Bye, Alex

 

[Mula]

The paper is proposing a role for p53 but none of those studies or any other has taken a look at p53 levels, so there should be no expectation for p53 to not be similar to cancer levels.

 

[Annikki]

You should know that p53 has been found to play a critical role in an autoimmune condition comorbid to ME, called Interstitial Cystitis:

p53 Mediates interstitial cystitis antiproliferative factor (APF)-induced growth inhibition of human urothelial cells
Jayoung Kim,a,b Susan K. Keay,c Jordan D. Dimitrakov,a,b and Michael R. Freemana,b,*
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The publisher's final edited version of this article is available free at FEBS Lett
See other articles in PMC that cite the published article.

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Abstract
Antiproliferative factor (APF) is a sialoglycopeptide elevated in the urine of patients with interstitial cystitis, a urinary bladder disorder of unknown etiology that is characterized by chronic pelvic pain. The present study was directed toward uncovering a pathway through which APF signals. Treatment of human urothelial cells with native APF resulted in growth inhibition accompanied by blockade of cell cycle transit and increased p53. Reduced expression of p53 by RNA interference diminished, while ectopic expression of p53 mimicked, the effects of APF. These are the first findings implicating the network of p53 target genes in urothelial defects associated with interstitial cystitis.
Keywords: Antiproliferative factor, Interstitial cystitis, Human urothelial cell, p53, p21Cip1/Waf1
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1. Introduction
Interstitial cystitis (IC) is a chronic bladder disorder with long-term symptoms of pelvic and or perineal pain, thinning or ulceration of the bladder epithelial lining, urinary frequency, and urgency. IC patients are generally diagnosed by the presence of certain clinical criteria in the absence of other identifiable causes for the symptoms (e.g., urinary tract infection). Although, there are multiple hypotheses about the primary cause of IC, the underlying molecular mechanism of IC remains completely undefined [1].
Three urine biomarkers for IC have been identified in published reports: the EGFR/ErbB1 peptide ligands, heparin-binding epidermal growth factor-like growth factor (HB-EGF), and epidermal growth factor (EGF) [2-4], and a novel sialoglycopeptide, named antiproliferative factor (APF) [3,4]. HB-EGF and EGF are present under normal conditions in human urine, but their concentration varies in a statistically significant and inverse manner (EGF levels are higher and HB-EGF levels are lower) in patients with IC as compared to their age-, race- and gender-matched controls [4]. APF, a low molecular weight, glycosylated peptide related to the membrane receptor frizzled-8, was purified from the urine of IC patients [5]. Bioactivities attributed to APF include: suppression of urothelial cell proliferation; increases in transcellular permeability; lowering of the expression of proteins that form intercellular junctional complexes; and reduction in the production of HB-EGF from urothelial cells [2,4,6-9]. APF/antiproliferative activity is detectable in the urine of approximately 95% of IC patients (as compared to approximately 9% of controls) [2-4]. This accumulation in urine of a bioactive factor, capable of altering the behavior of urothelial cells, is consistent with the clinical observation of epithelial thinning and denudation observed in IC bladder tissue [10,11].
The cell cycle regulatory protein, p53, is an essential mediator of cell cycle transit, apoptotic cell death, and cellular responses to stress [12,13]. p53 is a transcription factor that controls the expression of numerous genes in a network that is presently being defined using multiple approaches. In response to stressful environmental conditions, p53 protein levels rise, leading to cell cycle arrest or apoptosis. Loss of p53 function by mutation has been found to be the most common genetic alteration observed in human cancer cells, implying p53 as a suppressor of hyper-proliferation [12,13].
Because of its atypical features, the signaling mechanisms by which APF induces its anti-proliferative activity are of considerable interest. We show here that treatment of normal human urothelial cells, and T24 human bladder carcinoma cells, with APF increases p53 levels and that experimentally induced changes in p53 levels alter the APF effect on cell growth, indicating that p53 is involved in the mechanism of APF-induced growth suppression observed in the context of IC.

This calls to mind the cancers associated with ME/CFS. I always find there's always much to be learned if you don't just study CFS, but all the other disorders comorbid with it. There are too many similarities between the conditions comorbid to ME/CFS, such as fibromyalgia. I research pretty much everything, not CFS. One breakthrough in a disease associated with ME/CFS can possibly yield a breakthrough in ME/CFS, especially in terms of therapies.