Cytokine-Receptor concepts

[saham.kh]

Hi

I am a MSc student of control engineering at Control and Intelligent Processing Center of Excellence-School of Electrical and Computer Engineering.

I'm working on the modeling and simulation of brain lesion dynamics in multiple sclerosis as my final thesis.I'm trying to get familiar with medical texts, so please forgive me for my probable mistakes in asking my questions.

 

Here i am asking about the binding of the cytokines to their receptors on the cell surface. I've faced with texts like for example interleukin-12 binds to its receptor on T cells and initiates a change in the cell performance. I want to know that :

 

Is there a unique IL-12 receptor ( i mean one receptor ), or many IL-12 receptors that distributed on the cell surface? If there is many, how it is quantitated on the cell surface ( for example concentration of receptors on the cell surface) ?

 

Consider that the cell is exposed to 2 different kinds of cytokines with 2 different effects ( and maybe with opposite effects ),and the two cytokines are presented around the cell with the same concentrations. Which one will determine the final performance of the cell? Is there any kind of stochastic phenomenon that determine the final task of the cell ? Are the concentrations of receptors crucial for the fate of the cell? What will happen if we assume the case that the number of two different receptors ( or concentrations of them ) on the cell surface are also the same?

 

What do determine the High or Low affinity of the Receptor/cytokine binding? and does it play the crucial role for the fate of the cell ? what will happen if the affinities of the two different cytokines are exactly the same ?

 

I appreciate your taking the time to read or answer the questions.

[Variola]

Hiya

 

 

This is slightly out of my depth, but I can answer a few point that might help.

There are usually more than one receptor for a type of interleukin on the cell surface, however some interleukins, when they are bound cause the cell to express more receptors of a particular type of interleukin, and so increasing the chance of binding and activating intracellular signalling, the cast of IL12 i is the JAK_STAT pathway. It can also induce the decreased expression of other IL receptors, and sometimes cause the intracellular deactivation of other IL receptors. ( you would have to check exactly how as I can't remember!)

*As I understand it, T cells are all or nothing when it comes to IL signalling, which means they don't usually have two conflicting cytokine signals while being in an 'undecided' state. In other words, they usually receive a signal from one IL receptor, and they go down that pathway doing whatever they need to do, unless they get a signal telling them otherwise, often from a regulatory T cell that dampens down the immune response.

Plus it is not always just a single step signal, IL12 for example induces naive T cells to become Th0 cells, and then only after that to they become Th1 or 2 cells depending on what they encounter

Affinities are usually defined by the structure of the receptor, and with T cells the arrangement of alpha and beta chains whilst they mature in the thymus, therefore they will need very little of one cytokine to have an effect and a much higher concentration of another. This affinity regulation is important so the cell responds competently to the given situation. So if the concentration of two cytokines were the same, it would not matter as the key receptors with their own affinity for the cytokines with determine what happens.

 

*Denotes someone may give you a better or more correct answer to this one!

 

 

HTH

[Greippi]

The whole process of signalling (e.g. binding of a cytokine to a receptor and initiating a response in the cell) is very complex, so I'm going to give you some very broad simple answers that should help.

 

Is there a unique IL-12 receptor ( i mean one receptor ), or many IL-12 receptors that distributed on the cell surface? If there is many, how it is quantitated on the cell surface ( for example concentration of receptors on the cell surface) ?

I'm not entirely sure about this one with this specific example, but I would assume there are more than one. A cell can alter the number of receptors it expresses on its surface, the more receptors it has, the more receptive the cell will be to what the receptors bind. Since signalling pathways are very complex, there will have been another molecule along the line that determines how many receptors are expressed on the cell surface.

For example, there are certain conditions under which a cell would want to be more receptive to a certain signal, than other times.

 

Consider that the cell is exposed to 2 different kinds of cytokines with 2 different effects ( and maybe with opposite effects ),and the two cytokines are presented around the cell with the same concentrations. Which one will determine the final performance of the cell? Is there any kind of stochastic phenomenon that determine the final task of the cell ? Are the concentrations of receptors crucial for the fate of the cell? What will happen if we assume the case that the number of two different receptors ( or concentrations of them ) on the cell surface are also the same?

Different receptors have different affinity for their ligands.

For example, HYPOTHETICALLY, we have a cell that signal A increases the rate of protein synthesis, and signal B represses protein synthesis. Since signal A causes huge amounts of energy to be put in to synthesising proteins, it is more important that this signal pathway is tightly controlled. In this hypothetical case, it would be worse for the cell to expend unneccessary energy.

Therefore, higher concentrations of signal A would be needed to produce an effect than signal B.

 

It goes further than that though, once the ligand is bound the the receptor, it sets off a signal cascade within the cell which involves interactions between many other proteins. This introduces different control points to ensure the cell responds to the signal appropriately.

 

SO, in your example, the cell would respond to whichever signal it deems "most important".

 

HOWEVER, it is extremely unlikely that the cell would encounter opposite cytokines in sufficient quantities to initiate a response at the same time.

 

What do determine the High or Low affinity of the Receptor/cytokine binding? and does it play the crucial role for the fate of the cell ?

The receptor protein makes many contacts with the ligand molecule. The more easily these contacts are made the higher the affinity. Also important are the times it takes for the ligand to stay bound to the receptor, the time it takes for the ligand to fall off the receptor, and how long it takes for another ligand molecule to bind.

Sometimes receptors are desensitised, so that even if more ligand binds, they do not respond to the signal and activate the signalling pathway within the cell.

There are other factors as well, but that's the simplest.

 

what will happen if the affinities of the two different cytokines are exactly the same ?

I answered that a bit above. It's unlikely. Someone may be able to provide input as to if this does ever happen, but I would assume that would be in rare cases.

[Variola]

The whole process of signalling (e.g. binding of a cytokine to a receptor and initiating a response in the cell) is very complex

 

Yep and we are mad enough to be studying it.....!!!