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
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") +
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.
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.
