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Is anyone familiar with meds that block IL-6 Trans-signalling?

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5
Research has indicated that IL-6 trans-signalling may very well be the mechanism responsible for Sickness Behavior and of course Inflammation in people with ME/CFS, Fibromyalgia, Multiple Sclerosis, Parkinson, Alzheimer's and other Autoimmune disorders. I have been very interested in learning if there are any pharmalogical interventions that have worked in blocking the IL-6 trans-signalling mechanism. I have attached an article published online in April 2023 that appears to represent current thinking. Has anyone out there had any experience with or knowledge about the following medications: Olamkicept, Tocilizumab, Sarilumab, or Siltuximab? Also, my son's Complex Disease physician, Dr. Chedda, has suggested he ask his Rheumatologist about a trial of Plaquenil. Has anyone had any success with this drug? Thanks and I hope some of you have information to share about these possible pharmalogical interventions.

https://www.nature.com/articles/s41577-023-00856-y
 

datadragon

Senior Member
Messages
389
Location
East Coast, USA
IL-6 has both inflammatory and anti-inflammatory effects and generally therefore has not been considered a good target for that reason and also targeting downstream signalling effectors such as Janus kinases (JAKs) can have the same issue. That is interesting in the article that they may be able to only inhibit the inflammatory side of IL-6 at some point more selectively and worth looking at what they have available and develop, but for the moment the research I see has been more through inhibiting NLRP3 inflammasome activation (and subsequent IL-1b and IL-18 production and therefore preventing downstream effects (of which I have lists of dozens of potential ways to do that), or through AT1R receptor, or specific cytokines like IL-1a or TNF-a all within the earlier stages where inflammation is currently still high.

"none of these IL-6 signalling inhibitors can discriminate between classic signalling and trans-signalling, and they block both pathways simultaneously. As already mentioned, and described in detail in the next section, IL-6 trans-signalling has turned out to be the pathological arm of IL-6, whereas classic IL-6 signalling often seems to be protective and anti-inflammatory. "
 

datadragon

Senior Member
Messages
389
Location
East Coast, USA
Thank you for your response. I will continue to look at research and report back to the forum.
Ok.

Forgot to add: The activation of the NLRP3 inflammasome, results in the processing and secretion of active Interleukin 1 (IL-1b) and IL-18. An IL-1/IL-6 signature increases neutrophils and C-reactive protein (CRP), whereas an IL-18/IFN-y signature is characterized by hyperferritinemia (excess of an iron storage protein called ferretin in the blood) and cytopenia. Cytopenia occurs when one or more of your blood cell types is lower than it should be. IL-1 induces IL-6 and a Th-17 immune response, whereas IL-18 induces IFN gamma (IFN) production by Th-1 lymphocytes. A key function of IL-18 is to cooperate with IL-12 in inducing IFN-y production from T helper cells and natural killer cells, leading to natural killer cell activation, T helper type 1 cell skewing, up-regulated antigen presentation, and antiviral and antitumor functions.

Each condition has its own secondary effects that come after the chronic inflammation. For example with alzheimers it is mainly the dysregulation of copper metabolism through deficiency/unavailability of zinc and vitamin A that are involved in ceruloplasmin production needed for both copper and iron. Serum free copper is elevated in Alzheimers, correlates negatively with cognition in AD (the higher the free copper, the poorer the cognition) and is also a predictor of the degree of future cognition loss (the higher the free copper, the greater the rate of future cognition loss). Free copper is the part of blood copper not covalently bound to ceruloplasmin (Cp).

Regulating copper in the brain stops memory loss in a mouse model of Alzheimer's. Alzheimer's disease is characterized by the presence of amyloid plaques in the patient's brain. These plaques sequester copper, and contain approximately five times as much as a healthy brain. A new molecule extracts the copper trapped in amyloid plaques, and reintroduces it in the brain's normal enzymatic circuit (which needs copper to function). Administered orally to an Alzheimer's mouse model, this molecule inhibits the memory loss among sick mice. https://medicalxpress.com/news/2020-12-copper-brain-memory-loss-mouse.html https://www.pnas.org/content/109/5/1737 The low usable copper will then also affect iron causing unbound iron to build up and can also cause a deficiency of iron at the same time. The addition of only 0.12 parts per million of copper to the drinking water of several animals significantly enhanced brain levels of amyloid-beta and learning deficits and about twice as much copper in the cells lining the blood vessels of their brains, causing the AD pathological changes in the brain.

In drinking water samples from 280 households about a third of these samples had levels above 0.1 ppm copper, the level causing AD-type toxicity in animal models. Another third were at intermediate copper levels of unknown toxicity, and only one-third were at a level we consider completely safe, that is 0.01 ppm or less and also linked to the increase in inorganic copper ingested through water piping, copper sulfate sprayed on crops, copper iud, copper supplements, and passed down through the placenta. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4030141/ Then you have the dysregulation from inflammation that negatively has an effect on the organic and bioavailable (usable) copper.
 
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Messages
5
I have read some articles about these processes, but need to read more. I feel I have a pretty good understanding of classical IL-6 signalling and IL-6 trans-signalling, but still trying to educate myself more. I am really interested in knowing if any current medications actually block the trans-signalling of IL-6, thus reducing pro-inflammatory effects, while leaving classical IL-6 signalling anti-inflammatory effects alone. I do see you have commented on this above. I really appreciate your information and will continue to research more. I have lots of articles, but would be very interested in any specific articles you or anyone else on the forum feel are enlightening.
 

datadragon

Senior Member
Messages
389
Location
East Coast, USA
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Osaca

Senior Member
Messages
344
There was a study targeting IL-6 in Long-Covid. I will see if I can find the infos and if my memory is indeed correct.
 

Hip

Senior Member
Messages
17,790
Update: It's a Tocilizumab trial. Tocilizumab is a monoclonal antibody against the IL-6 receptor

It looks like tocilizumab binds to both the soluble IL-6 receptor and membrane-bound IL-6 receptor.

That means it will inhibit both the undesirable pro-inflammatory pathway of IL-6, as well as its beneficial anti-inflammatory pathway.


IL-6 is a contradictory cytokine, because it has both pro-inflammatory and anti-inflammatory pathways:
  • The trans signalling IL-6 pathway is pro-inflammatory
  • The classical signalling IL-6 pathway is anti-inflammatory

Massive amounts of IL-6 are released during exercise, and this exercise-released IL-6 I believe goes down the classical pathway, creating beneficial anti-inflammatory effects. This anti-inflammatory classical pathway of IL-6 is thought could be in part responsible for the health benefits of exercise.

In IL-6 classical signaling, IL-6 binds to the membrane-bound IL-6 receptor found on cell membranes.

Whereas IL-6 trans-signalling functions via the soluble IL-6 receptor. A soluble receptor is one which is not attached to any cellular membrane, but which floats around freely in the blood.

In trans-signalling, IL-6 binds to the soluble IL-6 receptor (sIL-6R) floating about in the blood, and this combination of IL-6 + sIL-6R forms a complex. This complex can then attach to and activate the glycoprotein 130 (gp130) receptor on cells. So that's how trans-signalling works.

More into in this post.


So if you wanted to selectively inhibit just the pro-inflammatory pathway of IL-6, whilst leaving the beneficial anti-inflammatory pathway intact, you would want to just prevent IL-6 from attaching to the soluble IL-6 receptor.
 

datadragon

Senior Member
Messages
389
Location
East Coast, USA
IL-6 is a known downstream target of IL-1β as mentioned, and is consistently increased in serum from patients with NLRP3 inflammasome-mediated conditions. https://pubmed.ncbi.nlm.nih.gov/22904305/ Targeting of the NLRP3 inflammasome usually does a better job at reducing IL-1B/IL-6 (pro inflammatory) is just what I was trying to suggest.

Palmitoylethanolamide inhibits NLRP3 inflammasome expression (such as mentioned here expressed by sars-cov-2 spike protein). However it also helped with the gut barrier, restructuring the gut bacteria and short chain fatty acid profile, and inhibits STING so that was my first thought over some of the other options that appear to help from their NLRP3 inhibition which I can provide a list I started awhile ago.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8472716/ And of course sodium butyrate in later stages should help with the pem and energy as another thought I've mentioned so far.
 
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Messages
8
Location
Virginia Beach
It looks like tocilizumab binds to both the soluble IL-6 receptor and membrane-bound IL-6 receptor.

That means it will inhibit both the undesirable pro-inflammatory pathway of IL-6, as well as its beneficial anti-inflammatory pathway.


IL-6 is a contradictory cytokine, because it has both pro-inflammatory and anti-inflammatory pathways:
  • The trans signalling IL-6 pathway is pro-inflammatory
  • The classical signalling IL-6 pathway is anti-inflammatory

Massive amounts of IL-6 are released during exercise, and this exercise-released IL-6 I believe goes down the classical pathway, creating beneficial anti-inflammatory effects. This anti-inflammatory classical pathway of IL-6 is thought could be in part responsible for the health benefits of exercise.

In IL-6 classical signaling, IL-6 binds to the membrane-bound IL-6 receptor found on cell membranes.

Whereas IL-6 trans-signalling functions via the soluble IL-6 receptor. A soluble receptor is one which is not attached to any cellular membrane, but which floats around freely in the blood.

In trans-signalling, IL-6 binds to the soluble IL-6 receptor (sIL-6R) floating about in the blood, and this combination of IL-6 + sIL-6R forms a complex. This complex can then attach to and activate the glycoprotein 130 (gp130) receptor on cells. So that's how trans-signalling works.

More into in this post.


So if you wanted to selectively inhibit just the pro-inflammatory pathway of IL-6, whilst leaving the beneficial anti-inflammatory pathway intact, you would want to just prevent IL-6 from attaching to the soluble IL-6 receptor.
Hi, everyone! I'm drdemeter's son, the one with CFS. My mom is my caregiver, helping me out with everything since I'm in pretty bad shape most the time these days. Very thankful to have someone who is understanding and willing to help with research + getting me to facilities for treatments.

Hip, I posted at the bottom of that IL6 as a myokine thread. Good to see you here too.

We're very interested in learning about and discussing:
  • the sickness behavior mechanism and pathways that lead to triggering, especially since it really fits the central complaint of a "tired, flu-like sensation that doesn't improve with rest"... way better than "fatigue" describes it
  • IL6 trans-signaling, especially in the brain and possibly PNS (vagus nerve in particular since that meditates the fast signaling of sickness behavior)
  • meds that can block IL6 trans-signaling
  • generally elucidating the pathways & SB mechanisms that shut us down, to see where things can go wrong in ways that could be causing the multitude of CFS/FM symptoms
I think we have a major combo problem with 1️⃣ our inherent weak sensation of sickness behavior (as in "this cold completely snuck up on me" or "I feel tired all the time, like I'm getting over the flu") + 2️⃣ the standard treatment is to fix whatever the other thing is that's causing it, or simply wait it out until we get better.

Even though we've been describing sickness behavior to doctors all along, they naturally won't respond much to something that's supposedly downstream of some possibly real problem, especially if there's no treatments for them to even try. And if we don't feel the symptoms strong enough to complain loudly and repeatedly & don't know that this weak sensation could actually be our problem... Well, we all know how that goes.

If there's a strong, well-preserved evolutionary mechanism that doesn't help us function healthily, but instead shuts us down and causes the exact symptoms we've been describing all along, then why are we all ignoring it? Why aren't we learning everything about it and demanding research that fills in the The missing pieces? Do we seriously not want to know?

I think once we become more aware of it and notice the sensation, the feeling of needing to rest and wait until we get better, of wanting to take care of ourselves, work, and do stuff but our effort getting snuffed out despite our motivation... We'll realize that we at least need to verify there's actually nothing wrong there, instead of going along with the unproven standard assumption that it's not even something to check out.

That's what led me to look into how sickness behavior works. That taught me about how IL1b, TNFa and IL6 are the main actors in the humoral signaling of SB, and the vagus nerve transmits the other neural signal. A key to this is that the signals must make it to our CNS.

I haven't gotten much farther in researching how these signals work in the brain to induce SB, and which neurons, transmitters, metabolics, etc are involved. (The first article, by Dr Danzer, I linked in the IL6 myokine thread goes into some detail)

Attempts to use meds to inhibit IL6b and TNFa didn't work to halt SB. Inhibiting both can be deadly. IL6 initially seems off track (especially since it's a healthy myokine that floods our circulation after strenuous exercise), but trans-signaling suddenly makes it seem incredibly relevant.

The review article in Nature's Immunity section drdemeter linked in the OP has a lot of good info about IL6 trans-signaling that fits in line with what I've been thinking. It also covers the current meds that work on various stages of trans-signaling, starting about halfway through.

Check out this image from that article that shows the potential sites of action. At the left are the antibody-based meds that work on IL6 and IL6R. But towards the right there are some that work on the IL6+sIL6R complex and even one that blocks the ADAM17 splicing mechanism that turns membrane bound IL6R (mIL6R) to soluble sIL6R.
Screenshot_20230720-115729-139.png

Ah I grabbed the article PDF from the site and am attaching it here for ease. Also the Danzer sickness behavior summary.

Okay, I'm running out of steam. Sorry for a lengthy and kind of insistent post. I really hope people get interested in diving into this more and especially that helps us some answers and relief.
 

Attachments

  • s41577-023-00856-y.pdf
    3.8 MB · Views: 4
  • 1. Cytokine Sickness Behavior and Depression nihms119940.pdf
    299.5 KB · Views: 3
Messages
8
Location
Virginia Beach
IL-6 is a known downstream target of IL-1β as mentioned, and is consistently increased in serum from patients with NLRP3 inflammasome-mediated conditions. https://pubmed.ncbi.nlm.nih.gov/22904305/ Targeting of the NLRP3 inflammasome usually does a better job at reducing IL-1B/IL-6 (pro inflammatory) is just what I was trying to suggest.

Palmitoylethanolamide inhibits NLRP3 inflammasome expression (such as mentioned here expressed by sars-cov-2 spike protein). However it also helped with the gut barrier, restructuring the gut bacteria and short chain fatty acid profile, and inhibits STING so that was my first thought over some of the other options that appear to help from their NLRP3 inhibition which I can provide a list I started awhile ago.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8472716/ And of course sodium butyrate in later stages should help with the pem and energy as another thought I've mentioned so far.
This sounds like it might be connected to the trans-signaling mechanisms. Even if not, it's something I should learn more about, especially the NLRP3 inflammazone. Thanks for this!
 

Hip

Senior Member
Messages
17,790
This post details the four known pathways by which peripheral inflammation is detected, and the information transmitted to the brain in order to activate sickness behaviour.
 
Messages
28
Haven't read the complete information here, but while looking at the question in the title I thought I remembered something about the supplement Resveratrol. I've done a search and came up with this:
Resveratrol suppresses interleukin-6 expression through activation of sirtuin 1 in hypertrophied H9c2 cardiomyoblasts

From personal experience I know that taking Resveratrol decreases the physical tiredness and even mental one. After a few days of 200 mg Resveratrol I seem to have more motivation to follow through with tasks(whereas I normally make big plans and just abandon them), I am more focused and my mind is more clear. For me there are some downsides also and that is the reason I don't continue to take it every day.
 

Dmitri

Senior Member
Messages
219
Location
NYC
I tried sarilumab injections for a period of about four months and unfortunately didn't get any benefit. On the final month of trialing it, I caught a severe intestinal infection which may or may not have been exacerbated by the immunosuppressive effects of IL-6 inhibition.
 
Messages
5
Interesting information about sarilumab, which is one of the medications I wanted to know about. I understand from articles I have read and from posts on this forum, that some medications do block IL-6 trans-signalling, but also interfere with IL-6 classical signalling, which may cause severe problems like the one described with sarilumab. Does anyone have any experience with Olamkicept? I have several articles, but am only referencing one short one below This is a quote from the article: “Olamkicept, a first-in-class, selective inhibitor of the s-interleukin-6R/IL-6 complex, is a dimer formed by fusing two complete extracellular domains of gp130 to human IgG1Fc that inhibits IL-6 trans-signaling by binding to and neutralizing the sIL-6R/IL-6 complexes but does not block classic IL-6 signaling,” Any thoughts?

https://www.healio.com/news/gastroe...ponse-in-nearly-60-of-patients-with-active-uc
 

pattismith

Senior Member
Messages
3,926
Ok.

Forgot to add: The activation of the NLRP3 inflammasome, results in the processing and secretion of active Interleukin 1 (IL-1b) and IL-18. An IL-1/IL-6 signature increases neutrophils and C-reactive protein (CRP), whereas an IL-18/IFN-y signature is characterized by hyperferritinemia (excess of an iron storage protein called ferretin in the blood) and cytopenia. .
I'm interested in this hyperferritenemia theory, but I can't find any study linking IL-18/IFN-y to hyperferritinemia....(or to reduced hepcidin level).

On the other hand I can find many studies linking IL-1 beta and/or IL-6 to high hepcidin (reduced iron absorption) and inflammatory anemia.

The only interesting study I found is in Gaucher Disease hyperferritinemia: it makes a link between local increase of hepcidin in spleen macrophage by local inflammation/ increased local IL-1b (and normal IL-6) and hyperferritinemia.


It's a french study released in 2018:
https://www.haematologica.org/article/view/8412