The Cytokines of the Immune System

The Role of Cytokines in Disease Related to Immune Response

Zlatko Dembic

• Publisher: Academic Press
• Year: 2015
• ISBN:
  9780124200104
• Topic: Medicina
• Subtopic: Immunologia

The Cytokines of the Immune System catalogs cytokines and links them to physiology and pathology, providing a welcome and hugely timely tool for scientists in all related fields. In cataloguing cytokines, it lists their potential for therapeutic use, links them to disease treatments needing further research and development, and shows their utility for learning about the immune system. This book offers a new approach in the study of cytokines by combining detailed guidebook-style cytokine description, disease linking, and presentation of immunologic roles.

• Supplies new ideas for basic and clinical research
• Provides cytokine descriptions in a guidebook-style, cataloging the origins, structures, functions, receptors, disease-linkage, and therapeutic potentials
• Offers a textbook-style view on the immune system with the immunologic role of each cytokine

Chapter 1

Introduction—Common Features About Cytokines

Abstract

The chapter is an introduction about cytokines. The molecular structure, sources of production and secretion, receptors, signal transduction, and function are described in general terms. Cytokines are products of many cells mostly including those of the immune system that can be secreted upon a stimulus or an activating event at various locations. Their similarities and dissimilarities with hormones are described.

Keywords

Structure; Function; Receptors; Signal transduction; Hormones; Cytokines

Cytokines are cell-to-cell messengers similar to hormones with the strongest activity in the microenvironment of the cells that secrete them. The majority have an immunomodulating effect and this book focuses on them. The name cytokine derives from Greek cyto (cell) and kinos (movement), implying their role in cellular traffic (e.g., towards sites of infection). Differences between endocrine hormones and cytokines are mentioned later in the Introduction.

Structurally and genetically, cytokines are defined as polypeptides, proteins, and glycoproteins, unlike some other heralds in the microenvironment, such as prostaglandins, which have a different structure. The physiological role of cytokines, in general, is in tissue homeostasis and cellular activation, relocation and differentiation. The oldest described functions were in regulating the immune system’s response to trauma, inflammation, and infection. However, the details about actions for the majority of cytokines are still largely unknown. Many diseases show aberrant communication between tissues and the immune system that involves cytokines. Research about the action of cytokines is therefore essential for the understanding of their pathophysiology. As this part of biomedical research is very dynamic, facts concerning the function of cytokines are increasingly accumulating in the scientific and clinical literature.

In a number of cases, abnormalities in cytokines’ actions were found either as a cause or effect of a disease, and therefore responsible for all or part of the symptomatology. For this reason, this book lists current available knowledge about the link between various diseases and immunomodulating cytokines hoping to facilitate further research. In addition, it is expected that new knowledge about cytokine function will promote the advancement of medical diagnosis and therapy.

Cells within tissues with well-known architecture typically communicate with each other through direct contact using molecules (mostly glycoproteins) imbedded in their cellular membranes. Examples are inhibition of growth in differentiated solid tissues, or by electrochemical signals such as those in the heart, muscle, and brain. Cytokines, on the other hand, are generally produced as a consequence of cell activation. They serve as communicators for a variety of characteristic functions in specific tissues. They are important for local homeostasis including growth, differentiation, development, and interaction with other tissues and organs in the body. They act in most cases at shorter distances (with exceptions such as IL-1, IL-6, “insulin like growth factors” [IGF], TNF and a few more). However, cytokines penetrate most tissues, being delivered by migration of white blood cells of the hematopoietic tissue, which permeates virtually all other tissues in vertebrates. This delivery method is influenced by a specialized set of cytokines called chemokines. The latter are important not only for regulating white-blood-cells’ traffic but also for the activation and coordination of certain immune reactions. Unfortunately, this latter area seems to be very complicated, because the regulation of the immune system is not completely understood. It is assumed that cytokines hold the “key” of the remaining unknowns in immune responses, as well as diseases related to disorders of immunity.

Therefore, in order to understand the function of cytokines one needs to have knowledge of the biology of cells of various tissues as well as of the functioning of the immune system, which is described in the first part of the book. The vast majority of cytokines are very important for growth, development, and mobilization of immune cells as well as for the creation and regulation of effector functions in the immune response to infections, organ transplants, and autoimmune diseases. Furthermore, the immune competent cells are one of the largest sources of cytokines that with their ability to migrate in almost all tissues of the body represent moving regulators of the local microenvironment.

Throughout history, functional principles in biology were learned and based on studies of diseases and their pathophysiological processes. Similarly, a large number of disorders, in which cytokines were a cause or a consequence of a disease, have been described. Most of them have an immunological sign.

Immunological disorders are divided into (a) congenital and acquired immunological deficiencies; (b) autoimmunity; (c) allergy (as a result of insufficient, incorrect, or exaggerated immune system reactions); and (d) the damage that is caused by secondary somatic primary disease or unknown cause (idiopathic). Of secondary disorders it is important to mention neoplasias of the immune system (lymphomas and leukemias) and primary diseases of various organs that result in failure of immunity. Malignant tumors of solid tissues, according to the theory of immune surveillance, develop as a result of impaired immunity or its lack. However, the sole emergence of cancer cells is a process in which the immune system probably does not have a direct impact. It is possible that in the process of cancer development (cellular transformation) caused by teratogenic viruses (or some yet unknown combination of microorganisms), a chronic immune response against such cancer cell can be a continuous stimulus for secretion of some cytokines. The latter might indirectly promote tumor development by the selection of more malignant mutations.

Division

Cytokines are divided into several groups of molecules bearing different names that tend to illustrate their functions. However, many have retained older names that describe only a minor portion of their activities like tumor necrosis factor (TNF) or transforming factor. When their collection of activities were discovered they were not re-named, although their relatives bear names that are signs of a group like interferons, interleukins, chemokines, or factors that affect growth and development of various tissues. There is no unified agreement on how to categorize cytokines and this book might provide help in this matter. I kept the division of cytokines according to their group names, and only a minority are presented with their original name. Their belonging to a specific group is mentioned under the subsection about their function, and basically, we can distinguish cytokines that have effects on hematopoietic (blood forming) tissues from those that do not, but directed towards other somatic tissues.

Structure

Cytokines are products of one to several genes that appear as monomeric or polymeric polypeptides and proteins, which are usually glycosylated. The most common forms are dimers (homodimers or heterodimers) and trimers (homotrimers and heterotrimers).

Examples of structures are shown in the Figure 1-1. As the monomer, interleukin-1 (IL-1) is a typical representative of this group. There are antagonists of cytokines such as IL-1 receptor antagonist (IL-1Ra) and IL-18 binding protein (IL-18 BP) that prevent the binding of cytokine to their receptor. Some cytokines such as transforming growth factor-β (TGF-β) are secreted in the intercellular space in an inactive form. Their activation involves an enzymatic process that produces an active part of the molecule. Since the TGF-β is everywhere in the body and constitutively secreted by many types of cells, the regulation of its activity is influenced by tissue-specific proteases.

Figure 1-1 Schematic exemplars of various structures of cytokines.

Of dimers, a representative is interferon-γ (IFN-γ), which is a homodimer. लhe active form of IFN-γ has two molecules that are set in antiparallel position, according to the crystallographic studies. Heterodimers are mostly interleukins, of which the most interesting exemplars (regarding the structure) are IL-12, IL-23, IL-27, and IL-35, because they cross-share a part of their molecule. Each has two subunits encoded by different genes. However their composition varies, as each is a combination of different subunits. This increases a potential to exert specific effects in different locations (or tissues) through regulation of expression of each particular subunit. For example, IL-12 and IL-23 share a common heavy subunit (p40), while the lighter subunits p35 (of IL-12) and p19 (of IL-23) can be differently regulated. Furthermore, p40 subunit can form homodimers, and it is considered that such a cytokine (so far unnamed) has an antagonistic effect on both, IL-12 and IL-23 cytokines. Furthermore, IL-27 is also composed of two similar subunits, and shares one with IL-35 (the latter includes the IL-12 p35 subunit). The complexity in interleukin structure probably reflects their multifaceted role in the regulation of immune responses.

The most representative trimer is the TNF. Its structure is a molecular triangle formed by three monomers. The...