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

[Sherlock]

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.

 

[Snow Leopard]

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]

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]

@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.

 

[Sherlock]

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]

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.

 

[Sherlock]

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]

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]

@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]

@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]

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.

 

[kangaSue]

Inhibiting IL-6 may be part of the reason why nitrates help in some cases of CFS.

Some potassium channel activators open the mitoKATP channel which participate in the regulation of microglial proinflammatory activation. Recent research is showing that nitrates have the same capability

http://www.hindawi.com/journals/omcl/2013/194546/
http://ncbi.nlm.nih.gov/pmc/articles/PMC2651423/

 

[Hip]

This quote copied from another discussion on IL-6:

Damn, I should have known you'd already been there.

When I read some years back that IL-6 increases by 100-fold after exercise, I thought that has got to explain PEM. But it looks like ME/CFS researchers had already investigated this idea, as the study I mentioned investigated the IL-6 pathways in ME/CFS patients at rest and after exercise. So they got there before me!


Though I don't fully understand these two IL-6 pathways, the classical signaling and trans-signaling pathways, and how exercise-secreted IL-6 only goes down the anti-inflammation classical signaling pathway.

It is the soluble IL-6 receptor in the blood which determines which pathway is taken by the IL-6, but the amount of soluble IL-6 receptor in the blood does not change much after exercise. This paper says:

High intensity and long duration exercises induce a large plasma level increase of interleukin-6 (IL-6), and a modest increase in soluble IL-6 receptor (sIL-6R)

So what I don't quite understand is how the 100-fold increase in IL-6 after exercise only goes down the classical pathway, and not the trans pathway.

Though possibly the preference for the classical pathway might because after massive amounts of IL-6 are released by exercise, the soluble IL-6 receptor gets saturated, and so can no longer send IL-6 down the trans pathway.

 

[Dufresne]

PEM has always been a brain thing for me. Certainly physical exertion can cause it but it seems to revolve around dysregulation, mood problems, fatigue, weakness, etc, but this is perceived as central, rather than peripheral. I don't ever have muscle complaints as part of PEM.

As IL-6 can cross the BBB I wonder if exercise-induced increases in IL-6 could be exacerbating inflammation in the brain. I do know that when I take immunomodulators that increase cellular immunity I develop a drastic lowering of my PEM threshold along with mood issues, and then symptoms further downstream from there. Sitting down and doing nothing is the only way to stabilize my mood at such times. It seems to me IL-6 could be an important crossover cytokine.

@Hip the study you linked to involving IL-6 in ME/CFS patients used blood samples. I can't help but wonder what a similar study using CSF might turn up, or one looking at soluble IL-6 receptors in the CSF of people with ME.

The Wikipedia entry for IL-6 seems to be suggesting it's a priming by TNF-a that causes IL-6 to go down the inflammatory pathway. Perhaps TNF-a increases soluble IL-6 receptors? I admit this kind of stuff is not my forte, and I appreciate all sufficiently dumbed down explanations.

 

[Hip]

@Hip the study you linked to involving IL-6 in ME/CFS patients used blood samples. I can't help but wonder what a similar study using CSF might turn up, or one looking at soluble IL-6 receptors in the CSF of people with ME.

The Wikipedia entry for IL-6 seems to be suggesting it's a priming by TNF-a that causes IL-6 to go down the inflammatory pathway. Perhaps TNF-a increases soluble IL-6 receptors? I admit this kind of stuff is not my forte, and I appreciate all sufficiently dumbed down explanations.

I have only investigated IL-6 to the level I detailed in this thread, and have not gone any deeper than that; just trying to understand the soluble IL-6 receptor mechanism. So I don't really know any more about this subject that what I have already mentioned.

I guess one way to test the IL-6 PEM theory would be to inject ME/CFS patients with the typically amount of IL-6 that is produced by exercise. If that triggers PEM, then it would prove IL-6 involvement. If it did not, then it would suggest PEM is not linked to exercise-induced IL-6.

 

[Wishful]

When I read some years back that IL-6 increases by 100-fold after exercise,

Did you come across a timeframe for IL-6 increase? IFN-g rises 24 hrs after exertion, so that matched my 24 hr delay for physically-induced PEM. Whichever cytokine it was, it was a consistent 24 hr delay. I assume that some cytokines have a variable delay.

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.

EPO also has high levels of cis-linoleic acid, which improves my sleep, as did ruminant fats which also contain the cis isomer. It's not as simple as "x contains omega-3, therefore that's why it works". You could try some beef or lamb fat and some other omega-3 source to see which one provides the noticeable benefit.

 

[Hip]

Did you come across a timeframe for IL-6 increase? IFN-g rises 24 hrs after exertion, so that matched my 24 hr delay for physically-induced PEM. Whichever cytokine it was, it was a consistent 24 hr delay. I assume that some cytokines have a variable delay.

I just found this paper which says:

resistance training acutely upregulates IL-6 by up to 100-fold, and the peak of IL-6 level is reached at the end of the exercise or shortly after, about 30 minutes after the exercise, followed by a rapid decrease towards pre-exercise levels.5

If interferon gamma increases 24 hours after exercise, that seems to more closely match the known delayed appearance of PEM.

 

[Wishful]

@Hip Another experiment you might find interesting or useful is to see whether safflower oil works as well for you as EPO. It does for me, for improving my time between wakings. It's rich in cis-linoleic acid, and is cheaper and works for cooking.

 

[Hip]

@Hip Another experiment you might find interesting or useful is to see whether safflower oil works as well for you as EPO. It does for me, for improving my time between wakings. It's rich in cis-linoleic acid, and is cheaper and works for cooking.

Thanks, I will look into safflower oil.

 

[stephencollier]

When I read some years back that IL-6 increases by 100-fold after exercise, I thought that has got to explain PEM. But it looks like ME/CFS researchers had already investigated this idea, as the study I mentioned investigated the IL-6 pathways in ME/CFS patients at rest and after exercise. So they got there before me!


Though I don't fully understand these two IL-6 pathways, the classical signaling and trans-signaling pathways, and how exercise-secreted IL-6 only goes down the anti-inflammation classical signaling pathway.

It is the soluble IL-6 receptor in the blood which determines which pathway is taken by the IL-6, but the amount of soluble IL-6 receptor in the blood does not change much after exercise. This paper says:



So what I don't quite understand is how the 100-fold increase in IL-6 after exercise only goes down the classical pathway, and not the trans pathway.

Though possibly the preference for the classical pathway might because after massive amounts of IL-6 are released by exercise, the soluble IL-6 receptor gets saturated, and so can no longer send IL-6 down the trans pathway.

Not sure if there's a better place to jump into the IL-6 trans-signaling + sgp130 topic, but I've put it off way too long and just need to start. I've got a bunch of (possibly quite significant) info to add to this, so if I don't get too much done now, please keep prodding me! heheh

Honestly, I'm just glad there are people that are at all familiar with IL-6 trans-signaling! I think we should put together an article to make a strong case for trying a treatment by directly administering sgp130 into the brain. (This treatment successfully eliminated sickness behavior in mice suffering from LPS-induced sickness)

I honestly think this has a strong possibility for being a solution (or part thereof) for many, if not all, of us suffering from CFS, fibro, and possibly many more pathologies. In fact, I'd bet much like to volunteer to be the first guinea pig for the treatment.

Still, I haven't learned enough for a complete picture. I need to read the attached articles again and fully read some. And then learn more about connected things. But I've become too shut down to make much progress for months. I really could use help with this or to hand it off to those who can take over. Verify if I've got this straight and research more to fill in the gaps.

Here's an initial summary for part of this that I'm writing on the fly here...

First, I should say I don't think blood levels of sIL-6R are relevant for sickness behavior. It's sIL-6R in the brain that counts. Only a few types of brain cells have IL-6 receptors, but many have gp130 receptors that can bind the sIL-6R + IL-6 complex, which is the trans-signaling mechanism. That list of brain cells is a bit longer. So classic IL-6 signaling only happens with a few types of brain cells while IL-6 trans-signaling involves many, presumably meditating sickness behavior.

If @Dufresne is correct that IL-6 can cross the BBB, then significant exercise will increase IL-6 in the brain. I don't know specifically if muscle-generated IL-6 can participate in trans-signaling. It'll do classical signaling for anyone, but the presence of sIL-6R in the brain should be the first of two factors that primarily determine trans-signaling and, presumably, the sickness behavior mechanism. Article 2 I've attached has some nice diagrams for this.

I haven't yet seen something that says this, but I have to infer that the second factor is the presence of soluble gp130 in the brain. Sgp130 inhibits IL-6 trans-signaling by binding the IL-6R+IL-6 complex so it can't bind to the gp130 receptors on many types of brain cells. This mechanism stops sickness behavior in mice, which don't natively produce sgp130. It's human sgp130 that works for them. Article 3 is that study.

So, IL-6 production and circulation is fine and normal, unless there's significant amounts of sIL-6R in the brain + not enough sgp130 to block it. The sickness behavior mechanism is also fine and normal (hell, it's a well-preserved evolutionary mechanism for mammals), unless it doesn't stop or there's too much of it outside normal sickness.

Sickness behavior is exactly what pwcfs have been describing all these years, but it's a blind spot because it's normal. The treatment is to find out what the "real" pathogenesis is. The sickness behavior will stop by itself (often without our despite treatment). This, sickness behavior is normal and will naturally go away, not something to treat.

On top of this, since sickness behavior is an evolved survival mechanism, people naturally think it's good for us. Healthy. However, it only helps us to survive some situations. Or it helps our kin by not letting us spread sickness to them. There's nothing it helps us for healthy functioning, It's a set of sickness functions for crying out loud.

It's just that there's so many known ways that sickness behavior gets triggered. How can it be possible that none of those pathways will ever go wrong for anybody? And with multiple pathways that signal what about the aggregate of all the signals? Really, doesn't it come down to not if but how much sickness signaling we have at any given time?

Attached article 4 is some general IL-6 info, more as a myokine, I think. There might be a little graph of the post exertion circulation levels of some cytokines that seem to like up with PEM.

-----
Okay I've run outta steam. I've got more thoughts on this, but this seems like a good start for me and a good continuation for this conversation. I hope this makes sense to everyone. Like a lot of sense. (I hope I'm not thinking crazy here, heheh). I hope some of you are encouraged to run with this and it's on the right track and we can get things moving towards getting our real lives back.