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

Discussion in 'Post-Exertional Malaise, Fatigue, and Crashes' started by Sherlock, Jan 15, 2015.

  1. Sherlock

    Sherlock tart cherry etc. for joints, insomnia

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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


    http://www.ncbi.nlm.nih.gov/pubmed?db=PubMed&term=23897689
    Compr Physiol.
    Muscle as a secretory organ.
    2013


    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
     
  2. Snow Leopard

    Snow Leopard Hibernating

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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.
     
  3. Sherlock

    Sherlock tart cherry etc. for joints, insomnia

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    I'd like to read through any past discussions here of IL-6 as being anti-inflammatory.Can you point out any?
     
  4. Hip

    Hip Senior Member

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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. 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. 1

    Furthermore, inhibiting IL-6 trans-signaling prevents LPS-induced sickness behavior. 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. 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. 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, 1 in ME/CFS soluble IL-6 receptor levels were found to be normal. 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.

    Or does it? Perhaps under exercise conditions, blood levels of the soluble IL-6 receptor might get altered in ME/CFS patients.
     
    Last edited: May 9, 2015
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  5. Sherlock

    Sherlock tart cherry etc. for joints, insomnia

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    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.
    That's from 1998. https://www.ncbi.nlm.nih.gov/pubmed/9715251

    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.

    Well, maybe sIL-6 needs to be tested during PEM - instead of testing baseline levels. Check this out:
    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:

    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.
     
  6. Hip

    Hip Senior Member

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    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:

    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.
     
    Last edited: Mar 8, 2017
  7. Sherlock

    Sherlock tart cherry etc. for joints, insomnia

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    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
     
  8. Sherlock

    Sherlock tart cherry etc. for joints, insomnia

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    Check out this mind-emotion<->immune-sytem connectoin:
    http://www.jleukbio.org/content/64/2/135.long

    Okay, thanks; I guess that kills IL-6 --- but then raises F(2)-isoprostanes as a suspect.
    So that leaves out COX-inhibitors... and puts focus on arachidonic acid.

    and
    @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.)
     
  9. Hip

    Hip Senior Member

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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.
     
  10. Sherlock

    Sherlock tart cherry etc. for joints, insomnia

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    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..
     
  11. Hip

    Hip Senior Member

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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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  12. kangaSue

    kangaSue Senior Member

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    aaron_c and Hip like this.

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