Why inflammation goes on too long

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Why inflammation goes on too long

Postby TwistedHelix » Sat Jun 30, 2007 6:12 am

The article below is a real tongue twister, but it brings together quite a few things which keep cropping up in relation to MS: TNF-alpha, arachidonic acid, (which is part of the glutamate cascade), the Rho proteins and oxidants. It shows how they work together to prevent white blood cells from clearing away dead cells and thus prolong inflammation. We already know that inflammation can be protective in the short term but is a source of damage if it goes on too long.

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J Immunol. 2007 Jun 15;178(12):8117-26.
McPhillips K, Janssen WJ, Ghosh M, Byrne A, Gardai S, Remigio L, Bratton DL, Kang JL, Henson P
Discuss | category: Immunology


Removal of apoptotic cells from inflammatory sites is an important step in the resolution of inflammation. Both murine and human macrophages stimulated with TNF-alpha or directly administered arachidonic acid showed an impaired ability to ingest apoptotic cells (efferocytosis). The inhibition was shown to be due to generation of reactive oxygen species, was blocked with a superoxide dismutase mimetic, MnTBAP, and was mimicked by direct addition of H2O2. To determine the mechanism of TNF-alpha-stimulated oxidant production, bone marrow-derived macrophages from gp91(phox)-deficient mice were examined but shown to still produce oxidants and exhibit defective apoptotic cell uptake. In contrast, a specific cytosolic phospholipase A2 inhibitor blocked the oxidant production and reversed the inhibited uptake. The suppressive effect of endogenous or exogenous oxidants on efferocytosis was mediated through activation of the GTPase, Rho. It was reversed in macrophages pretreated with C3 transferase to inactivate Rho or with an inhibitor of Rho kinase. During maturation of human monocyte-derived macrophages, only mature cells exhibited TNF-alpha-induced suppression of apoptotic cell clearance. The resistance of immature macrophages to such inhibition was shown to result not from defective generation of oxidants, but rather, from lack of response of these cells to the oxidants. Overall, the data suggest that macrophages in a TNF-alpha- and oxidant-rich inflammatory environment are less able to remove apoptotic cells and, thereby, may contribute to the local intensity of the inflammatory response
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Inflammation

Postby bromley » Sat Jun 30, 2007 9:01 am

Dom,

Thanks for the post.

This is sort of related - a response given to me by Dr Alasdair Coles (Mr Campath) during a Q&A on the MS Society website. Part of his response to my question was as follows


But we have made some observations that are relevant. For instance, we –as others - have noted that the immune cells from people with multiple sclerosis do not die as quickly as they should (by a programmed suicide system called “apoptosis”). This is important because one way of stopping an immune attack is for the immune cells themselves to die. And we know that all people (with or without multiple sclerosis) have immune cells that react against myelin. Perhaps getting multiple sclerosis is simply down to a defect in the mechanism that causes immune cells to die off…..

If so, one way of treating multiple sclerosis might be to restore the mechanism of apoptosis. We have some information on this, but it is too early to go public on an open website!
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Re: Inflammation

Postby Lyon » Sat Jun 30, 2007 5:40 pm

bromley wrote: For instance, we –as others - have noted that the immune cells from people with multiple sclerosis do not die as quickly as they should (by a programmed suicide system called “apoptosis”). This is important because one way of stopping an immune attack is for the immune cells themselves to die.
In this MS environment in which nothing seems to make sense, it's nice to finally hear something imminently sensible! :lol:

I can't say it would be an easy thing to get them to die when they're supposed to, but knowing one actual "fact" is a great improvement from the past.
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Postby gwa » Sun Jul 01, 2007 6:28 am

bromley,

Would you ask Dr Coles how one might restore the mechanism of apoptosis?
Is this mechanism being studied now?

Sounds very intriguing!

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Postby TwistedHelix » Sun Jul 01, 2007 10:45 am

The subject of Apoptosis is an interesting and, (surprise, surprise!), complicated one.
The mitochondria of neurons contain a protein called Apoptosis Inducing Factor which kills the cells by binding to the DNA. It does this in response to an external signal, which, if we could control it, might be one way of switching Apoptosis on or off.
The gene p53 might be another area to look at: it's normal role is to suppress tumours by inducing Apoptosis in cancerous cells. Some viruses can suppress the action of this gene and guess what? Our old friend the Epstein Barr Virus produces a couple of proteins which suppress Apoptosis.
TNF-alpha and oxidants are both capable of inducing Apoptosis.
Cells will also commit suicide if they don't continuously receive signals telling them to stay alive.


I have to say that the following sentence:
We have some information on this, but it is too early to go public on an open website!


Sounds really promising!
Last edited by TwistedHelix on Mon Jul 02, 2007 4:20 am, edited 1 time in total.
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Postby Lyon » Sun Jul 01, 2007 11:01 am

We'd make quite a team Dom, kind of like Batman and Robin.

Those you can't dazzle with your brilliance, I'll baffle with my bull!
WHACK!! POW!! BOOM!! ZAP!!
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Postby TwistedHelix » Mon Jul 02, 2007 5:03 am

Wow, Bob,
You look much slimmer than I expected... Not too sure about the tights though... they're just sooo last year!

As usual, I entered a post and then immediately felt as if I hadn't made myself clear: I was trying to answer your point, gwa, by saying that at least there is some knowledge about Apoptosis, though whether that knowledge is complete or will ever lead to treatment is anybody's guess. Your quote from Dr. Coles, Ian, gives a very tantalising hint that the answer might be " yes"
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