THE CYTOKINES

Cytokines are a group of proteins produced by different cells, especially cells of the immune system, either as a response to an immune stimulus or as an intercellular signal after a certain stimulation. Cytokines have a multitude of different biological effects and are very important both in the innate and in the adaptive immune  response.  

The generic name of cytokines includes all proteins, usually glycosylated and with a small molecular weight, released by cells of the immune system, especially by monocytes and T lymphocytes. But they are also secreted by many cells in addition to those of the immune system, such as endothelial cells and fibroblasts. They used to have different names depending either on their origin, such as lymphokines (produced by lymphocytes), monokines (monocytes) or on their activity: chemokines, interleukines, interferon. 

It is well known nowadays, that the same cytokine can be produced by different cells, and even that the same cytokine can perform different functions. This is why the classification based on the cell of origin or the function is not used anymore, and these substances are now generically known as CYTOKINES. They include all substances secreted by the different cells and all the different functions. 

During the last decade, and due to the development of new molecular techniques that have allowed the cloning of many cytokines as well as their analysis and quantification, the knowledge of structural and functional aspects of cytokines has been extraordinarily developed, especially in the human and murine species. Porcine cytokines have also been studied in the last years, and a great number of them are now well known. In this chapter we will study the structure, function and measurement of cytokines, giving special attention to porcine cytokines.    

Cytokines are chemical messengers or hormones; they are extremely potent and act at very low concentrations. They are very specific, and act through specific receptors of the target cell membrane.

The cytokine receptors are membrane glycoproteins consisting on several units. They have the role of internalization of the signal . This initiates a cascade of  intracellular signaling  with many proteins involved. Among them, kinases of the JAK family, which attract and activate the transcription factors of the STAT family. The result of this chain reaction is the induction of several genes that mediate the biological activities of cytokines. Besides membrane receptors, soluble receptors for different cytokines have been found in sera; they are similar to the membrane receptors and are found in  large quantities. It is thought that their function is the regulation of the cytokine production, and to act as antagonists of the membrane receptors.   

CYTOKINE RECEPTORS. MECHANISMS OF ACTIVATION

1. Cytokine binding to the cell receptor. 

2.- Dimerization of the receptor and JAK kinase activation: phosphorylation of the receptor.

3.- Phosphorylation and dimerization of SATS; activation of the transcription of target genes 

Cytokines activity:  A: Autocrine; E: Endocrine; P: Paracrine. The activity of Cytokines is mainly local (autocrine and paracrine) and in a lower proportion, endocrine. 

The role of cytokines is sometimes similar to that of hormones, and this is why cytokines are also known as the hormones of the immune system.  Cytokines are involved in the innate immune response because they induce macrophage and NK cell activation, generating inflammatory and chemotaxis processes.  They also play a role in the adaptive immune response when they act on T and B lymphocytes, favoring the communication among different cell populations. The main difference between cytokines and hormones is that cytokines have their effect on different cell populations and tissues, while hormones usually act on just one organ. Moreover, a single cell can produce different cytokines, and this does not happen with hormones. . 

Lastly, cytokines usually act locally, both in the cell producing them (autocrine activity) and in the cells next to it (paracrine activity). More rarely they have an effect on cells and tissues distant from the place where they are produced (endocrine activity). This is similar to hormones. However, some cytokines, especially those with inflammatory effects such as IL-1 and TNF have their effect after being transported through the blood to distant target cells (endocrine activity).  

HOW MANY TYPES OF CYTOKINES ARE KNOWN?

In the last few years several types of cytokines have been newly described, and some of them have been cloned. Thus, in the human and murine species 36 cytokines have been cloned, although only 19 are available from the porcine species. 

The different cytokine families are grouped in accordance to their receptor type, although due to the fact that different receptors are linked to different activities the classification of cytokines includes both structural and functional aspects.  The cytokines IL 2, IL 4, IL 7, IL 9 and IL 15 share the same receptors and have a common function. They have a g chain receptor (g_c CD 123) which is related to the activation of the T lymphocytes growth. Cytokines IL 3, IL 5 and GM-CSF share the receptor of the b chain (b_c) which is related to the proliferation and differentiation of the hematopoietic precursors. 

From a functional point of view, cytokines are classified in two different groups with activities and mechanisms that we will cover under the following subjects:

• Mediators of Innate Immunity and Inflammation. 

• Mediators of Hematopoiesis.

• Mediators of Chemotaxis.

• Mediators in the activation, proliferation, differentiation and death of T and B lymphocytes.