Hello everybody!
I thought I would share my research on cytokines and ME/CFS. My interest in this area was sparked by the recent transcriptome study that found the following genes over expressed:
We can take note of Il-8 a cytokine (and chemokine), TNF induced protein and Nf-kB Inhibitor A. This last gene seems to be unregulated by NF-kB as a negative feedback mechanism, [2] so high inhibitor of kB suggests high NF-kB.
IL-8
Now lets look at a recent paper by KDM looking for potential biomarkers:
"The best model included the sCD14, PGE2, IL-8"
Another point for IL-8, and we also note the Prostaglandin E2. Lets look at fibromyalgia research to see what we can learn:
Evidence of different mediators of central inflammation in dysfunctional and inflammatory pain — Interleukin-8 in fibromyalgia and interleukin-1 β in rheumatoid arthritis
Evidence of central inflammation in fibromyalgia-increased cerebrospinal fluid interleukin-8 levels.
So the importance of IL-8 seems to be clear.
TGF
Now lets turn to the Montoya Study:
"only two cytokines were found to be different (TGF-β higher and resistin lower) in ME/CFS patients"
What? No IL-8? KDM explains in his paper that due to the different IL-8 isoforms, and ELISA test used, results can vary dramatically. Are there any ME/CFS studies that can back up an elevated TGF level?
Increased neutrophil apoptosis in chronic fatigue syndrome
Patients with CFS had significantly higher levels of neutrophil annexing V and TNF-RI expression (37.4 vs 22.8%, p=0.001 [Mann-Whitney U-test]; and 12.5 vs 3.9%, p=0.004; respectively) and increased plasma levels of TGF-b1 (2.24 vs 1.89 pg/mL, p=0.005) when compared with controls
Up-regulation of TGF-β1 mRNA expression in peripheral blood mononuclear cells of patients with chronic fatigue syndrome.
The mean value of TGF-β1 mRNA expression in CFS patients was ΔΔCt=1.17±0.58, which was significantly higher than the disease controls (ΔΔCt=0.07±1.08, df=111, p < 0.01) and the healthy controls (ΔΔCt=0.00±1.63, df=111, p < 0.01)
Chronic fatigue syndrome and circulating cytokines: A systematic review
Cases of CFS had significantly elevated concentrations of transforming growth factor-beta (TGF-β) in five out of eight (63%) studies. No other cytokines were present in abnormal concentrations in the majority of studies
So IL-8 and TGF stand out as being predictors of ME/CFS, with the possible addition of PGE2 and TNF, all of them probably mediated by NF-kB. Now comes the interesting part. In what diseases are these cytokines upregulated?
The effects of Ang-1, IL-8 and TGF-β1 on the pathogenesis of COPD
We found statistically significant differences in the expression levels of Ang-1, IL-8 and TGF-β1 between the stable and acute phases
Exhaled leukotrienes and prostaglandins in COPD
There is a selective increase in exhaled LTB4 and PGE2 in patients with COPD which may be relatively resistant to inhaled corticosteroid therapy
Bare with me, I'm not crazy. Let's look at the recent FM transcriptome study
Thats right. Just after Liver and OXPHOS sits COPD. What could this mean? I don't know yet. But - eosinophils have been associated both with asthma and COPD. What is there to learn about eosinophils and ME/CFS? Lipkin to the rescue
Cytokine network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome
Group-specific differences were found for the majority of analytes with an increase in cases of CCL11 (eotaxin), a chemokine involved in eosinophil recruitment
COPD in the brain? God only knows. But, studies may give us some hints:
Transforming growth factor-β stimulates the expression of eotaxin/CC chemokine ligand 11 and its promoter activity through binding site for nuclear factor-κβ in airway smooth muscle cells.
TGF-beta1 stimulates IL-8 release, COX-2 expression, and PGE(2) release in human airway smooth muscle cells.
(cox catalyzes PGE2 formation)
Finally, assuming eosinophils are a problem, some druggable targets:
Regulation of Serotonin-Induced Trafficking and Migration of Eosinophils
Association of the neurotransmitter serotonin (5-HT) with the pathogenesis of allergic asthma is well recognized and its role as a chemoattractant for eosinophils (Eos) in vitro and in vivo has been previously demonstrated
Eosinophilic gastroenteritis in a young girl--long term remission under Montelukast
Montelukast reduces peripheral blood eosinophilia but not tissue eosinophilia or symptoms in a patient with eosinophilic gastroenteritis and esophageal stricture
During treatment with montelukast, the mean peripheral blood eosinophil count fell from 5,064 cells/microL to 1,195 cells/microL
---------------------------------------------------------------------------------------------
This is as far as I have gotten. I hope someone can take this info and connect it to other pieces of the puzzle. Lets do this!
(@mariovitali We need your algorithms. Perhaps a new run taking into consideration these findings?)
I thought I would share my research on cytokines and ME/CFS. My interest in this area was sparked by the recent transcriptome study that found the following genes over expressed:
We can take note of Il-8 a cytokine (and chemokine), TNF induced protein and Nf-kB Inhibitor A. This last gene seems to be unregulated by NF-kB as a negative feedback mechanism, [2] so high inhibitor of kB suggests high NF-kB.
IL-8
Now lets look at a recent paper by KDM looking for potential biomarkers:
"The best model included the sCD14, PGE2, IL-8"
Another point for IL-8, and we also note the Prostaglandin E2. Lets look at fibromyalgia research to see what we can learn:
Evidence of different mediators of central inflammation in dysfunctional and inflammatory pain — Interleukin-8 in fibromyalgia and interleukin-1 β in rheumatoid arthritis
Evidence of central inflammation in fibromyalgia-increased cerebrospinal fluid interleukin-8 levels.
So the importance of IL-8 seems to be clear.
TGF
Now lets turn to the Montoya Study:
"only two cytokines were found to be different (TGF-β higher and resistin lower) in ME/CFS patients"
What? No IL-8? KDM explains in his paper that due to the different IL-8 isoforms, and ELISA test used, results can vary dramatically. Are there any ME/CFS studies that can back up an elevated TGF level?
Increased neutrophil apoptosis in chronic fatigue syndrome
Patients with CFS had significantly higher levels of neutrophil annexing V and TNF-RI expression (37.4 vs 22.8%, p=0.001 [Mann-Whitney U-test]; and 12.5 vs 3.9%, p=0.004; respectively) and increased plasma levels of TGF-b1 (2.24 vs 1.89 pg/mL, p=0.005) when compared with controls
Up-regulation of TGF-β1 mRNA expression in peripheral blood mononuclear cells of patients with chronic fatigue syndrome.
The mean value of TGF-β1 mRNA expression in CFS patients was ΔΔCt=1.17±0.58, which was significantly higher than the disease controls (ΔΔCt=0.07±1.08, df=111, p < 0.01) and the healthy controls (ΔΔCt=0.00±1.63, df=111, p < 0.01)
Chronic fatigue syndrome and circulating cytokines: A systematic review
Cases of CFS had significantly elevated concentrations of transforming growth factor-beta (TGF-β) in five out of eight (63%) studies. No other cytokines were present in abnormal concentrations in the majority of studies
So IL-8 and TGF stand out as being predictors of ME/CFS, with the possible addition of PGE2 and TNF, all of them probably mediated by NF-kB. Now comes the interesting part. In what diseases are these cytokines upregulated?
The effects of Ang-1, IL-8 and TGF-β1 on the pathogenesis of COPD
We found statistically significant differences in the expression levels of Ang-1, IL-8 and TGF-β1 between the stable and acute phases
Exhaled leukotrienes and prostaglandins in COPD
There is a selective increase in exhaled LTB4 and PGE2 in patients with COPD which may be relatively resistant to inhaled corticosteroid therapy
Bare with me, I'm not crazy. Let's look at the recent FM transcriptome study
Thats right. Just after Liver and OXPHOS sits COPD. What could this mean? I don't know yet. But - eosinophils have been associated both with asthma and COPD. What is there to learn about eosinophils and ME/CFS? Lipkin to the rescue
Cytokine network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome
Group-specific differences were found for the majority of analytes with an increase in cases of CCL11 (eotaxin), a chemokine involved in eosinophil recruitment
COPD in the brain? God only knows. But, studies may give us some hints:
Transforming growth factor-β stimulates the expression of eotaxin/CC chemokine ligand 11 and its promoter activity through binding site for nuclear factor-κβ in airway smooth muscle cells.
TGF-beta1 stimulates IL-8 release, COX-2 expression, and PGE(2) release in human airway smooth muscle cells.
(cox catalyzes PGE2 formation)
Finally, assuming eosinophils are a problem, some druggable targets:
Regulation of Serotonin-Induced Trafficking and Migration of Eosinophils
Association of the neurotransmitter serotonin (5-HT) with the pathogenesis of allergic asthma is well recognized and its role as a chemoattractant for eosinophils (Eos) in vitro and in vivo has been previously demonstrated
Eosinophilic gastroenteritis in a young girl--long term remission under Montelukast
Montelukast reduces peripheral blood eosinophilia but not tissue eosinophilia or symptoms in a patient with eosinophilic gastroenteritis and esophageal stricture
During treatment with montelukast, the mean peripheral blood eosinophil count fell from 5,064 cells/microL to 1,195 cells/microL
---------------------------------------------------------------------------------------------
This is as far as I have gotten. I hope someone can take this info and connect it to other pieces of the puzzle. Lets do this!
(@mariovitali We need your algorithms. Perhaps a new run taking into consideration these findings?)