GROWTH FACTORS

Tumour necrosis factor-alpha (TNF-α) is a cytokine that is very important in inflammation and cell death, and it is also produced by many cell types apart from leukocytes.

(A) One study, using antibodies specific to TNF-α that bind to TNF-α and hence BLOCK the action of TNF-α in animals, found that liver regeneration was impaired. This is presumably because the normal inflammatory cell response associated with regeneration was prevented by the lack of TNF-α activity.

(B) We tested to see if muscle regeneration was similarly affected in the absence of TNF-α activity in mice where the gene for TNF-α had been silenced i.e. TNF-α knockout (or null) mice. We expected to see that inflammation would similarly be impaired in the absence of TNF-α and hence muscle regeneration delayed. BUT, we found that inflammation and regeneration was completely normal.

There is a reasonable explanation for this unexpected finding. The question is:

• What is the difference between a situation (A) where the protein for TNF-α is PRESENT but its action is BLOCKED (by antibodies), compared to the situation (B) where no TNF-α protein is present?? Think about the whole complex in vivo environment and networks/interactions between different proteins/genes. Think about the concept of redundancy. This knockout mouse demonstrates that the absence of a key gene product does not have the predicted disastrous effect and this ‘lack of major effect’ has been seen with quite a lot of knockout mice (much to the dismay of the researchers who thought their favourite gene was so important).

• Can you think of another way of blocking the activity of TNF-α to produce a similar effect to (A)??. (You may be able to target this other aspect using 2 different strategies).

Updated: 07/03/07