MYOKINE --- IL-6 as muscle anti-inflammatory

Sherlock

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http://www.indiana.edu/~k562/articles/athero/Il-6 myokine Pederson 2006.pdf
TRENDS in Pharmacological Sciences Vol.28 No.4
Beneficial health effects of exercise – the role of IL-6 as a myokine
2007

Muscle-derived IL-6: the first myokine IL-6 is most often classified as a proinflammatory cytokine, although data also indicate that IL-6 and IL-6-regulated acute-phase proteins are anti-inflammatory and immunosuppressive and might negatively regulate the acute-phase response

http://www.ncbi.nlm.nih.gov/pubmed?db=PubMed&term=23897689
Compr Physiol.
Muscle as a secretory organ.
2013
Skeletal muscle is the largest organ in the body. Skeletal muscles are primarily characterized by their mechanical activity required for posture, movement, and breathing, which depends on muscle fiber contractions. However, skeletal muscle is not just a component in our locomotor system. Recent evidence has identified skeletal muscle as a secretory organ. We have suggested that cytokines and other peptides that are produced, expressed, and released by muscle fibers and exert either autocrine, paracrine, or endocrine effects should be classified as "myokines." The muscle secretome consists of several hundred secreted peptides. This finding provides a conceptual basis and a whole new paradigm for understanding how muscles communicate with other organs such as adipose tissue, liver, pancreas, bones, and brain.


http://www.nature.com/icb/journal/v92/n4/full/icb201416a.html
Immunology and Cell Biology
From cytokine to myokine: the emerging role of interleukin-6 in metabolic regulation
April 2014
The lack of physical activity and overnutrition in our modern lifestyle culminates in what we now experience as the current obesity and diabetes pandemic. Medical research performed over the past 20 years identified chronic low-grade inflammation as a mediator of these metabolic disorders. Hence, finding therapeutic strategies against this underlying inflammation and identifying molecules implicated in this process is of significant importance. Following the observation of an increased plasma concentration of interleukin-6 (IL-6) in obese patients, this protein, known predominantly as a pro-inflammatory cytokine, came into focus. In an attempt to clarify its importance, several studies implicated IL-6 as a co-inducer of the development of obesity-associated insulin resistance, which precedes the development of type 2 diabetes. However, the identification of IL-6 as a myokine, a protein produced and secreted by skeletal muscle to fulfil paracrine or endocrine roles in the insulin-sensitizing effects following exercise, provides a contrasting and hence paradoxical identity of this protein in the context of metabolism. We review here the literature considering the complex, pleiotropic role of IL-6 in the context of metabolism in health and disease.
 
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The old idea of 'pro/antinflammitory' is a bit simplistic, since a variety of signaling cascades can potentially be stimulated, since it is not just a single (or a few) cytokines that determines the response to a particular stimulus.
 

Sherlock

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The old idea of 'pro/antinflammitory' is a bit simplistic, since a variety of signaling cascades can potentially be stimulated, since it is not just a single (or a few) cytokines that determines the response to a particular stimulus.
I'd like to read through any past discussions here of IL-6 as being anti-inflammatory.Can you point out any?
 

Hip

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@Sherlock @Snow Leopard

I was reading about the Janus-faced pro-inflammatory and anti-inflammatory nature of IL-6 a while ago. Here is a summary of what I found:

Essentially, IL-6 can operate by two pathways, the classical signaling IL-6 pathway which is anti-inflammatory and instigates tissue repair, and the trans-signaling IL-6 pathway which is pro-inflammatory. Ref: 1

It seems to me that the IL-6 trans-signaling pathway might have significant import for ME/CFS. Inhibiting the pro-inflammatory IL-6 trans-signaling pathway is being considered as a treatment for various inflammatory diseases such as rheumatoid arthritis and atherosclerosis. Ref: 1

Furthermore, inhibiting IL-6 trans-signaling prevents LPS-induced sickness behavior. Ref: 1

Now in the context of Michael VanElzakker's vagus nerve theory of ME/CFS, which posits that ME/CFS symptoms are due to sickness behavior active by cytokines from an infection, the fact that blocking IL-6 trans-signaling eliminates sickness behavior suggests that if you were to block the trans-signaling IL-6 pathway, this might lead to a recovery from ME/CFS.

Inhibiting the pro-inflammatory IL-6 trans-signaling has also been shown to improve cognitive dysfunction and neuroinflammation in the elderly. Ref: 1


When IL-6 is released by the muscles during exercise, it normally has an anti-inflammatory effect. This IL-6 released by exercised muscles is classed as a myokine. A myokine is defined as a cytokine produced by muscles.

More info on IL-6 as a myokine here.



I wonder whether something may have gone wrong in ME/CFS, such that the IL-6 released during exercise somehow becomes pro-inflammatory rather than anti-inflammatory. This might explain why exercise causes post-exertional malaise in ME/CFS patients.


What could have gone wrong in ME/CFS to potentially make IL-6 pro-inflammatory rather than anti-inflammatory?

Well, let's look at how IL-6 trans-signaling operates: it functions via the soluble IL-6 receptor. A soluble receptor is one which is not attached to any cellular membrane, but which (I believe) floats around freely in the blood.

What happens in IL-6 trans-signaling is that IL-6 will bind to the soluble IL-6 receptor (sIL-6R) floating about in the blood, and then this combination of IL-6 + sIL-6R form a complex. This complex can then attach to and activate the glycoprotein 130 (gp130) receptor on cells. Ref: 1

This contrasts to IL-6 classical signaling, in which IL-6 will bind to the regular IL-6 receptor found on cell membranes.

So basically the ratio of pro-inflammatory trans-signaling to anti-inflammatory classical signaling is controlled by the amount of soluble IL-6 receptors present in the blood. The more soluble IL-6 receptors are present in the blood, the more the pro-inflammatory trans-signaling IL-6 pathway is activated.


So, if there were an excess amount of the soluble IL-6 receptor floating about in the blood, that may have the effect of increasing the pro-inflammatory trans-signaling IL-6 pathway, and decreasing the anti-inflammatory classical signaling Il-6 pathway.

However, although significantly higher blood levels of the soluble IL-6 receptor have been found in ulcerative colitis and Crohn's disease (ref: 1), in ME/CFS soluble IL-6 receptor levels were found to be normal, both a rest and after exercise (ref: 1). So that probably puts an end to the idea that too much soluble IL-6 receptor might explain the inflammation found in ME/CFS.
 
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Sherlock

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A soluble receptor is one which is not attached to any cellular membrane, but which (I believe) floats around freely in the blood.
I knew that Enbrel/etanercept waas a soluble receptor - I didn't know until y menti0n it that soluble receptors are also natural and normal.
There is mounting evidence that soluble receptors play important roles in human disease states. In many cases, soluble receptors appear to play an integral part in the dynamic interaction between ligands and their membrane-bound receptors in maintaining and restoring health after a pathological insult but, in some instances, dysregulated expression of soluble receptors can contribute to disease pathology. Nonetheless, an appreciation of the biological actions of soluble receptors, particularly as cytokine inhibitors, has led to their therapeutic use in human diseases.
That's from 1998. https://www.ncbi.nlm.nih.gov/pubmed/9715251

atherosclerosis
Yep, after the huge interest in hsCRP from 2008's JUPITER trial with Paul Ridker, there came a registry study based in Italy that showed normal hsCR%P but elevated IL-6 in herat attack admissions.

So that puts an end to the idea that too much soluble IL-6 receptor might explain the inflammation found in ME/CFS.
Well, maybe sIL-6 needs to be tested during PEM - instead of testing baseline levels. Check this out:
However, although significantly higher blood levels of the soluble IL-6 receptor have ben found in ulcerative colitis and Crohn's disease, 1 in ME/CFS soluble IL-6 receptor levels were found to be normal. 1 So that puts an end to the idea that too much soluble IL-6 receptor might explain the inflammation found in ME/CFS.
http://www.jleukbio.org/content/64/2/135.long

It's known that neutrophis invade a muscle as a result of exercise. sIL receptors can maybe be the mechanism by which local inflammation becomes systemic and prolonged PEM, similar to what that paper describes:

soluble IL-4 receptor prolongs the half-life of IL-4 in the circulation and enhances the effects of IL-4 by serving as a binding protein
Later, sIL receptors can maybe act as a competitor to membrane bound IL receptors to quell inflammatin (in normals). It's alot of maybes... :)

Too bad there aren't home test kit available, it could be answered in a day or two.

I have repeatedly been suggesting that people who get PEM (I no nonger do) try taking anti-infammatories peri-workout, but so far.nobody will try that simple step. As you likely know, benefit from exercise in normals is blunted by anti-inflamatories like NSAIDs and stains - but in CFS such exogenous agents might he necessary to get into the Goldilocks zone wherein the amount of inflammation is reduced to where it is just right.
 

Hip

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I have repeatedly been suggesting that people who get PEM (I no nonger do) try taking anti-infammatories peri-workout, but so far.nobody will try that simple step. As you likely know, benefit from exercise in normals is blunted by anti-inflamatories like NSAIDs and stains - but in CFS such exogenous agents might he necessary to get into the Goldilocks zone wherein the amount of inflammation is reduced to where it is just right.
That certainly would be a very good experiment to try.

I mainly just get post-exertional malaise (PEM) from mental activities, particularly socializing, but not really from physical activities. I did try taking a cocktail of IL-6 inhibitors before going out to socialize, to see if these might reduce my PEM, but they did not. However, the mechanism of mental PEM may not be the same as the mechanism for physical PEM.

The cocktail of IL-6 inhibitors I took before socializing were the following:

IL-6 inhibitor Protocol:
Luteolin 100 mg
Idebenone 200 mg
Q10 200 mg
PABA 500 mg
Horny goat weed (Epimedium) 900 mg
Curcumin 900 mg
Vitamin D 10,000 iu
Vitamin E 400 mg
Pregnenolone 25 mg
Vitamin K 100 mg
Vinpocetine 30 mg
Genistein 56 mg
Daidzein 37 mg
Amla 2000 mg
Niacinamide 500 mg

It would be interesting to see if ME/CFS patients with physical PEM might benefit from these IL-6 inhibitors taken before physical exertion though.

Some study references for above IL-6 inhibitors:
Four macrolides (roxithromycin, erythromycin, clarithromycin and azithromycin) inhibited IL-1β, TNF-α, IL-6 LPS-stimulated J774 macrophages. 1 (full text). NOTE: Roxithromycin is the only macrolide antibiotic that crosses the blood brain barrier.
Macrolide antibiotics (like azithromycin and erythromycin) inhibit IL-6 1
Amoxicillin significant decreased IL-6 plasma levels by the 7th day of therapy. 1
Vitamin C and vitamin E inhibit muscle-derived IL-6. 1
Blueberries reduce TNF-α and IL-6 in mouse macrophages 1
Patchouli alcohol (from patchouli essential oil) inhibits IL-1β, TNF-α, IL-6 in mouse macrophages (RAW 264.7 cells) 1
Genistein inhibited LPS-induced IL-1beta, IL-6, and TNF-alpha expression in macrophages. 1
Vinpocetine inhibited the production of inflammatory factors such as IL-1β, IL-6 and TNF-α in BV-2 microglia. 1
Sulforaphane attenuates the LPS-induced increase of IL-1beta, IL-6, and TNF-alpha expression in microglia 1 Sulforaphane reduces TNF-α-induced IL-6 synoviocytes 1
Vitamin D inhibits LPS-induced IL-6 and TNF-α production in macrophages. 1
Cyclosporin A decreases human macrophage interleukin-6 synthesis. 1
Luteolin reduces IL-6 production in microglia. Luteolin: 90% drop in IL-6 production.1 Pretreatment of primary microglia with 10 and 25 μM luteolin reduced LPS-induced IL-6 production by 40% and 90%, respectively. When luteolin was increased to 50 μM, IL-6 secretion by LPS-stimulated microglia was completely blocked. If we take the bioavailability of luteolin to be 5%, then the dosage to achieve a 25 μM concentration is 25 x 286.24 / (55 x 250) = 520 mg of luteolin. NOTE: the lutein bioavailability when given as Chrysanthemum morifolium extract is 55.4%, but for pure lutein is may be much lower. 1
Alpha acids and iso-alpha acids in hops (found in beer) block the TNF-alpha induced production of IL-6. 1
Polyphenols in non-alcoholic beer reduce IL-6 1
Calendula officinalis (marigold) inhibits IL-1beta, IL-6, TNF-alpha and IFN-gamma. 1
Magnolia officinalis (Magnolia) Obovatol (from Magnolia) attenuates microglia-mediated neuroinflammation. 1
Niacinamide 1
Pyrroloquinoline quinone (PQQ) reduces IL-6 1

Well, maybe sIL-6 needs to be tested during PEM - instead of testing baseline levels.
I believe they did this in the study: "Blood samples taken in the submaximal test at rest, immediately post-exercise and 24 h post-exercise were analyzed for IL-6, sIL-6R, sgp130 and F(2)-isoprostanes."

But ME/CFS patients showed no increase in sIL-6R compared to controls.
 
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Sherlock

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What happens in IL-6 trans-signaling is that IL-6 will bind to the soluble IL-6 receptor (sIL-6R) floating about in the blood, and then this combination of IL-6 + sIL-6R form a complex. This complex can then attach to and activate the glycoprotein 130 (gp130) receptor on cells
So the it seems that also any IL can form such a complex and then bind to the generic gp130. This might explain how/why inflammation in the gut or from a common virus cold can set off systemic inflammation. E.g., sometimes after I have sugar my joints will suffer.

But, if this is true, how does knowing this help? (Aside from knowing to maybe take anti-inflammatories, preferably non-drug.)

Maybe exercise enhances one's ability to clear(or generate) sIL-Rs. But in the end, I don't personally think that the name of the molecule matters - an elemental ( :) ) approach dealing with inflammation and movement in cycles
 

Sherlock

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I mainly just get post-exertional malaise (PEM) from mental activities
Check out this mind-emotion<->immune-sytem connectoin:
Soluble IL-2 receptor levels have also been reported to be elevated in those who attempted suicide
http://www.jleukbio.org/content/64/2/135.long

But ME/CFS patients showed no increase in sIL-R compared to controls.
Okay, thanks; I guess that kills IL-6 --- but then raises F(2)-isoprostanes as a suspect.
The isoprostanes are prostaglandin-like compounds formed in vivo from the free radical-catalyzed peroxidation of essential fatty acids (primarily arachidonic acid) without the direct action of cyclooxygenase (COX) enzymes.
So that leaves out COX-inhibitors... and puts focus on arachidonic acid.

Through its conversion to active components such as the prostaglandin PGF2alpha and PGE2 after physical exercise, arachidonic acid is necessary for the repair and growth of skeletal muscle tissue.
and
Arachidonic acid is one of the most abundant fatty acids in the brain
Individuals suffering from joint pains or active inflammatory disease may find that increased arachidonic acid consumption exacerbates symptoms, presumably because it is being more readily converted to inflammatory compounds. Likewise, high arachidonic acid consumption is not advised for individuals with a history of inflammatory disease, or who are in compromised health. Of note, while ARA supplementation does not appear to have proinflammatory effects in healthy individuals, it may counter the anti-inflammatory effects of omega-3 fatty acid supplementation.
@Hip, have to tried n-6 as a PEM preventative?

I tend to bleed from fish oil because I have thin blood - but I will run a fish oil experiment today anyway to see if there is any quick-onset benefit. (Maybe also take some K-1 to see if that prevenrts bleeding, ie. when brushing my teeth.)
 

Hip

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@Sherlock
I found that evening primrose oil (which contains omega 6) helps reduce anxiety levels, and improves my sleep if taken just before bed, but I have not tried it for reducing mental PEM.
 

Sherlock

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@Sherlock
I found that evening primrose oil (which contains omega 6) helps reduce anxiety levels, and improves my sleep if taken just before bed, but I have not tried it for reducing mental PEM.
Sorry, that was my typo. I'd meant n-3, the Omega 3s.

I think I'l stop posting for a few days - I just don't have the impetus to cncenyate as I' e been ramping up exercise for a few days and I just don't have the desire to edit myself as I usually do..
 

Hip

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Yes, I have tried omega 3 in the form of cod liver oil (5 ml daily), but it does not help my mental exertion induced PEM.
 

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