Cytokines

Cytokines are tiny proteins that are secreted by both immune and non-immune cells to communicate with one another. Cytokines bind to receptors and trigger a response in the receiving cell. Oftentimes, cytokines promote activation, proliferation, and differentiation of immune cells, but they can do other things like help increase the body temperature - causing a fever.

Now, cytokines signal to other cells mainly through autocrine and paracrine signaling; but to a lesser extent, endocrine signaling can also be employed. Now, autocrine means the cell producing the cytokine is also the cell responding to the cytokine. An example is Interleukin-2, or IL-2 which is secreted by CD4+ T helper cells. IL-2 promotes the proliferation of T lymphocytes - including the CD4+ T helper cell that produced it. Paracrine means that the cytokine is produced by one cell and that it affects cells in the near vicinity. Once again, an example is IL-2 because it helps nearby CD8+ cytotoxic T cells proliferate. That’s important because the CD8+ cytotoxic T cells aren’t good at making their own IL-2. Finally, there’s endocrine, which is when the cytokine affects a cell that’s far away, perhaps in a different organ. An example would be the inflammatory triad of Interleukin 1-beta or IL-1beta, Interleukin-6 or IL-6, and Tumor Necrosis Factor-alpha, or TNF-alpha. These cytokines are produced by macrophages and dendritic cells. During acute inflammation, these cytokines travel to the liver and the brain. In response, the liver produces acute phase reactants like C-reactive protein and Mannose Binding Lectin, and the brain increases the body’s temperature, triggering a fever. At the same time, IL-1beta and TNF-alpha also help to recruit other immune cells to the site of injury, enhancing the inflammatory response.

Overall, there are 5 main classes of cytokines. The first and most varied group are the Interleukins, which are numbered in the order they were identified, so the numbers don’t tell us anything about what they do! It used to be thought that interleukins were only sent between leukocytes or white blood cells, but it turns out that they’re released and act on both leukocytes as well as non-leukocytes.

The second group are the Tumor Necrosis Factors or TNFs. TNFs are named because they were discovered by their ability to kill tumor cells, now known to be because they elicit inflammation and the inflammatory cells - neutrophils and macrophages - actually do the killing. TNF-alpha; TNF-beta, also called lymphotoxin alpha, or LT alpha; and lymphotoxin beta, or LT beta are known to have a wide variety of biological effects in the inflammatory response, including activating endothelial cells to upregulate expression of adhesion molecules and increasing vascular permeability.

The third group are the Interferons, and as their name implies - they interfere with processes like viral replication. There are two types of Interferons - Type I and Type II. Type I interferons include Interferon alpha and Interferon beta, and they’re usually produced by virally infected cells and some dendritic cells responding to the viral infection, in order to limit viral replication. Now, the only Type II Interferon is interferon gamma. This molecule is the most powerful macrophage activator, and it also activates CD4+ helper T cells, which then secrete their own interferon gamma and IL-2.

The fourth group includes the colony-stimulating factors. These cytokines bind to surface receptors on hematopoietic stem cells, causing them to proliferate and differentiate. Some examples include Granulocyte-Macrophage Colony stimulating factor or GM-CSF, which is a cytokine secreted by a wide variety of immune and non-immune cells, that stimulates the development of granulocytes and macrophages.

The fifth and final group includes the Transforming growth factors. There are more than 30 different TGFs, and the most important in the immune system is TGF-beta. TGF-beta is an inhibitory factor that suppresses proliferation and differentiation of various cells. It also helps CD4+ T cells to develop into a regulatory cell that can slow down or stop the overall immune response. You can think of TGF-beta as helping to put on the brakes.