TNFalpha signaling - Please help

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rachawilson
rachawilson's picture
TNFalpha signaling - Please help

Hello all-
I have some questions about TNFalpha that I am a little confused on.  When you have TNFalpha binding on the cell....how does the cell decide which route to take.  By route...I mean either inflammation or apoptosis.  I have been reading in the literature about this...and what I have found is that once TNFalplha binds to its cognate receptor...it can recruit different adaptor proteins such as FADD, TRADD, etc.  I know that FADD has a DED domain which can interact with the DED domain in procaspase 8 to activate it thus initiating apoptosis to happen.  On the other hand, I have found that if the right adaptor proteins are recruiting you can also activate NFkappaB which can then translocate into the nucleus and transcribe anti-apoptotic factors such as Bcl-2, c-FLIP, etc.  

I am pretty new to this topic so any help would be very much appreciated.  Honestly,  I am just overall confused how the cell knows which route to go after TNFalpha binding....or even FasL...Trail...etc...

Thread moved to inflammation sub-forum - Bishop

R Bishop
R Bishop's picture
This can get confusing, I

This can get confusing, I agree.  Its not uncommon for cytokines and growth factors to possess both growth stimulating and growth inhibitory abilities.  There are several ways to think about how this contradictory action might occur. I have no idea which one is correct, just food for discussion.

Possibility 1 -  The cell is "primed" to go down one pathway or another.  Consider a cell that is already recieving signals that something is "wrong" and is preparing to head down the apoptosis route. It stands to reason that adaptors are upregulated and awaiting a trigger like TNFalha to hit the cell and trigger a response.

Possibility 2 - The total amount of TNFalpha interacting with the cell could effect the response.  Threshold responses are common in vivo, but can be schewed greatly in in vitro experiments.

Possibility 3 - Related to #1 is environment.  The environment surrounding a cell is critical to its repsonse. Lots of cytokine activation studies are performed in vitro.  However in lots of cases the opposite result (inflammation activation vs apoptosis) is seen in in vivo models. This is a real danger in in vitro experiments and Ive seen it so many times in various fields.

Just a few general hypotheses that come to mind. Im sure there are others.

Bishop

heehawmcduff
heehawmcduff's picture
Hey,

Hey,

Great question.  As far as I know (and I may have missed something that has been published recently), nobody actually knows why or how a cell chooses to go down the death route or the pro-inflammatory route following TNF stimulation. 

It seems to me that FADD is the key molecule here in that (as you rightly pointed out), it can interact with death receptors and induce apoptosis/necrosis or, via TRADD, which can either cause apoptosis inhibition by recruiting and forming 'inhibitors of apoptosis' complexes, or by initiating NFkB and IkB. 

So, what you and Rusty have already said really hits the nail on the head.  Either way - this article makes for interesting reading for mechanism but, if you do happen to find out any more as to the reason a cell goes down a particular pathway....please post!!

Best wishes