Cytokines and Mucosal Immunology

One of my friends majoring in immunology once gave the impression that immunology students see the word "cytokine" a lot. He wasn't wrong.

Cytokines

So what are cytokines? Well, they're pretty small molecules, but they're also pretty important molecules. They are messengers of the immune system that are secreted by many different cells of the body, most notably immune system cells such as macrophages, lymphocytes and so on. Types of cytokines include interleukins, chemokines, tumour necrosis factor (TNF), interferons (IFN) and so on.

Most cytokines act locally, via autocrine signalling (to the self) or paracrine signalling (through interstitial fluid to nearby cells). There are, however, some cytokines that act via endocrine signalling (via circulation). Cytokines have a very high affinity for their receptors, and so only nanomolar concentrations are needed to have an effect. Once bound, they can activate a variety of intracellular signalling cascades. These are important in a range of different situations, from immune responses, inflammation, haematopoesis, cellular proliferation, cell differentiation and wound healing.

Be able to describe cytokine signalling

Cytokines, as mentioned in my PHAR2210 post on enzyme-linked receptors, signal via the JAK/STAT pathway. Cytokine receptors are bound to Janus kinases (JAKs). When cytokines bind, the receptors dimerise, which brings pairs of JAKs close together. This allows JAKs to phosphorylate each other (autophosphorylation), as well as phosphorylate other areas of the cytokine receptors' cytoplasmic domains. All of this phosphorylation provides a nice environment for STATs (signal transducer and activator of transcription) to bind and become phosphorylated by JAK. Phosphorylated STATs are then able to form dimers and translocate into the nucleus, where they initiate gene transcription.

Be able to describe the roles of key cytokines

Unfortunately it looks like there's going to be a lot of details to memorise here, so bear with me.

Firstly, here's an overview of some of the cytokines that are going to come up through the course. This is by no means an extensive list- there's 35+ different kinds of interleukins (IL) for example, but you don't see all of them on this list.

• Proinflammatory cytokines: IL-1β, IL-6, TNF-α
• Anti-inflammatory cytokines: IL-10, TGF-β (TGF = transforming growth factor)
• T-cell related cytokines: IL-2, IL-4, IL-12
• B-cell related cytokines: IL-4, IL-5, IL-7
• Interferons: Type I and Type II

What they do is (mostly) pretty self-explanatory, but I'm going to go into a bit more detail and explanation anyway.

Pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), as their name suggests, induce inflammation and activation of immune cells. They are made by most immune cells, particularly macrophages and dendritic cells. Unfortunately you can have too much of a good thing, and so if they're not properly controlled, they can release way too many cytokines- this is known as a "cytokine storm." Complications can arise due to the inflammation.

Anti-inflammatory cytokines (IL-10, TGF-β) are also pretty self-explanatory- they're mainly involved in shutting off and controlling the immune response. They can also activate immune cells that promote healing. The major producers of these are macrophages and T-cells. Just like pro-inflammatory cytokines, these can be problematic if too many are produced because then the immune response would be suppressed. The key here is balance between pro- and anti-inflammatory cytokines.

T-cell related cytokines (IL-2, IL-4, IL-12) function to support T-cell proliferation and activation. Some are made by T-cells, but not all: IL-2 and IL-4 are both made by T-cells (IL-4 by T-helper cells specifically- I think IL-2 is made by both helper and cytotoxic T-cells) but IL-12 is made by macrophages and dendritic cells.

B-cell related cytokines (IL-4, IL-5, IL-7) function to support B-cell proliferation and differentiation. So they're kinda like T-cell related cytokines, but for B-cells. IL-4 and IL-5 are actually made by helper T-cells, however, and play a large role in the allergic response. IL-7 is also not made by B-cells: instead it is made by stromal cells in the bone marrow, where it aids in B-cell development.

There are two main types of interferons: Type I IFN and Type II IFN. Type I IFN has two subtypes: IFNα and IFNβ. They are produced mainly by macrophages and dendritic cells, and help fight viruses. Type II IFN includes the subtype IFNγ, and is produced by T and NK cells in order to enhance immune responses.

Attributes of Cytokines

There are four main attributes of cytokines that you should know about:

1. Pleiotropy: The ability of one cytokine to be able to exert different effects on different cells.
2. Redundancy: Sometimes, multiple cytokines might all perform the same function.
3. Synergy: Cytokines can work together in order to cause something to happen (i.e. multiple different cytokines might be needed).
4. Antagonism: One cytokine might block the effects of another.

Cytokines in Mucosal Immune Responses

Cytokines can induce inflammation. They might do this, for example, if there's something wrong with your normal gut flora. If this isn't well controlled, however, this can result in a chronic inflammatory disease, such as IBD (Inflammatory Bowel Disease).

Sorry that that's such a shitty note to end on! (Yup, I just had to make that pun...)