Replication of Crohn's Disease-associated AIEC Within Macrophages is Dependent on TNF-α Secretion

[Dave Watson]

Adherent and invasive Escherichia coli (AIEC) associated with Crohn's disease are able to survive and to replicate extensively in active phagolysosomes within macrophages.

AIEC-infected macrophages release large amounts of tumour necrosis factor-alpha (TNF-α) and do not undergo cell death. The aim of the present study was to determine what benefit AIEC bacteria could gain from inducing the release of large amounts of TNF-α by infected macrophages and to what extent the neutralization of TNF-α could affect AIEC intramacrophagic replication. Our results showed that the amount of TNF-α released by infected macrophages is correlated with the load of intramacrophagic AIEC bacteria and their intracellular replication. TNF-α secretion was not related to the number of bacteria entering host cells because when the number of bacteria internalized in macrophage was decreased by blocking lipid raft-dependent and clathrin-coated pits-dependent endocytosis, the amount of TNF-α secreted by infected macrophages was not modified. Interestingly, dose-dependent increases in the number of intracellular AIEC LF82 bacteria were observed when infected macrophages were stimulated with exogenous TNF-α, and neutralization of

TNF-α secreted by AIEC-infected macrophages using anti-TNF-α antibodies induced a significant decrease in the number of intramacrophagic bacteria. These results indicate that AIEC bacteria use TNF-α as a Trojan horse to ensure their intracellular replication because replication of AIEC bacteria within macrophages induces the release of TNF-α, which in turn increases the intramacrophagic replication of AIEC. Neutralizing TNF-α secreted by infected macrophages may represent an effective strategy to control AIEC intracellular replication.
Source: http://www.medscape.com/viewarticle/759548

In one way or another, effective CD drugs reduce TNF levels in the gut. For example.

Corticosteroids can improve Crohn’s and corticosteroids inhibit TNF (1).
Naltrexone can improve Crohn’s and Naltrexone inhibits TNF (2).
Mesalamine can improve Crohn’s and Mesalamine inhibits TNF (3).
Enbrel, Remicade and Humira can all improve Crohn’s and all are anti-TNF drugs.
Ect.​

But where does the TNF come from? Both AIEC & MAP are linked to CD. Both prefer the gut and both infect macrophages. The infected macrophages produce high levels of TNF.

Now for some interesting questions.

1. Are MAP/AIEC infected-macrophages the primary source of TNF in the guts of CD sufferers?
2. If yes, how does the excess TNF cause the inflammation and ulcers and why don't they heal?
3. What about the extra-intestinal manifestations of CD, are they be linked to high-levels of TNF in the blood?
4. Is Crohn's all about excess TNF?

You can find insights/answers to these questions buried in the academic archives. Treasure hunt anyone?

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(1) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1534652/pdf/clinexpimmunol00080-0084.pdf
(2) http://www.ncbi.nlm.nih.gov/pubmed/15265541
(3) http://www.ncbi.nlm.nih.gov/pubmed/10029619

 

[Dave Watson]

Interestingly, if you go to this Abbott Labs' Humira page, you'll see this

In Crohn's disease, excess TNF attacks the intestines

Many patients with Crohn's disease produce too much of a protein called TNF (tumor necrosis factor) in their body. This excess TNF attacks the intestines and other parts of the gastrointestinal (GI) tract, and can cause them to become inflamed. This can result in the pain, diarrhea, and other symptoms of Crohn's disease.
Source: http://www.humira.com/crohns/how-humira-works.aspx​

According to Abbott TNF "attacks" the gut... so have we solved the mystery of the cause of Crohn's? AIEC/MAP infect immune cells, and the immune cells produce excess TNF which attacks the intestines? Unfortunately it's not that simple.

Abbott's statement about TNF is false. TNF does not attack anything. TNF is a signaling protein and as such cannot attack tissue or anything else.

With Abbott’s resources (financial, intellectual and physical), I believe they could cure Crohn’s... but they won’t. Crohn’s is a multi-billion dollar industry, in others words, it's a cash cow!

How about we email Abbott and tell them we probably know where the TNF is coming from, so can they focus their efforts on developing new antibiotics that kill bacteria in the infected immune cells instead of developing more drugs to suppress TNF?

I tried emailing them and got no response. I wonder why?