Cytokine Effector Functions in Tissues

Maria Foti,Massimo Locati

• Publisher: Academic Press
• Year: 2017
• ISBN:
  9780128042199
• Topic: Medicine
• Subtopic: Immunology

Cytokine Effector Functions in Tissues discusses the cytokines networks in the context of the specific-tissue environment. It is an up-to-date collection of articles that addresses the specific issue of how the cytokines are able to condition tissue specific homeostasis. The book helps the reader understand how cytokines network inside the tissues and highlights whether tissue-protection or exacerbation will be finally controlled. It describes the cytokines detected and regulated in different tissues, such as the brain, lungs, spleen, liver, pancreas and intestine, also addressing the issue of timing in specific cell types.

• Categorizes the cytokines based primarily on tissue and target cells
• Emphasizes different roles and outcomes observed during innate and adaptive response
• Represents a rapid guide to cytokines in health and disease in tissue and organ context
• Presents a different view on how known mediators may work if analyzed in a different perspective, determining the final outcome on tissue-specific target cells

Part I

Cytokine Biology Overview

Outline

Chapter 1 Introduction to Cytokines as Tissue Regulators in Health and Disease

Chapter 1

Introduction to Cytokines as Tissue Regulators in Health and Disease

Maria Foti, University of Milano-Bicocca, Milan, Italy

Abstract

Cytokines are powerful mediators of several biological processes and are highly regulated in the body. Chronic uncontrolled levels of such proteins can initiate and potentiate many pathologies, including autoimmunity and cancer. Cytokines shares basic properties: they are pleiotropic—a given cytokine may drive proliferation of a cell type and induce growth arrest in another cell type, they are redundant, and the cytokine network is tightly regulated and its alteration may lead to impaired tissue and cellular physiology. Currently, there is an emerging understanding of the role of cytokine in tissue homeostatic functional regulation and it is becoming clear that pathological conditions may develop from dysregulation of cytokines. Some organs seem more vulnerable to dysregulated cytokines networks than others, so it is becoming more and more important to study the cytokine network in the contest of tissue specificity. In addition, cytokines can act in concert with other tissue-specific signals. Therefore, unraveling the complexity of such network is extremely challenging as different organs have developed diverse strategies to cope with immune cell migration. Here, I summarize the basic knowledge on functional groups of cytokines and the role played in the context of tissue regulation in health and disease.

Keywords

Cytokines families; inflammation; immunomodulation; tissue homeostasis; cytokine therapeutics

Outline

Introduction 3

Biological Characteristics of Cytokines 4

Proinflammatory Cytokines 5

Regulatory Cytokines 10

Cytokines Important in T Lymphocyte Differentiation (Th1, Th2, Th22) 12

Cytokines Important in B Cells Differentiation and Activation 14

Cytokines and Tissue Homeostasis 15

Cytokines as Growth Factors 20

Immunomodulation by Cytokines in Human Diseases 21

Conclusion 24

References 25

Introduction

Cytokines are a complex of soluble, cell-signaling proteins that affect the biological function of cells and process such as inflammation, a variety of immune responses, and the wound healing activity. Cytokines include interleukins, chemokines, interferons, and growth factors. Although similar to hormones in that they act at low levels either systemically or locally, cytokines are unique in the large number of cells they are able to target. Cytokines are not restricted to any single organ or tissue but instead they are synthesized by a variety of hematopoietic cells, including myeloid (e.g., macrophages, dendritic cells (DCs), granulocytes, mast cells), lymphoid cells (e.g., B cell, T cells, natural killer cells) and by nonhematopoietic cells such as endothelial and epithelial cells. Different immune cells can secrete the same cytokines building up complex microenvironments that are functionally pro or antiinflammatory depending on the specific cytokine and cellular target present in that organ. In fact, a role of cytokines in certain organs is not yet fully determined, for example, the role of interleukin-1β (IL-1β) in normal physiology of the central nervous system still remains unclear. Therefore, understanding the basic of this network of interactions in a tissue-specific manner will advance our knowledge on cytokine biology to better exploit them in the context of clinical immunotherapeutic settings.

Biological Characteristics of Cytokines

There are over 100 cytokines and many exist in families that share receptor components and signal transduction pathways. Many diseases are characterized by complex cytokine networks that may have a positive or a negative impact on the disease.¹ Cytokines are low molecular weight molecule that possess some common properties: They have a short half-life, they are de novo synthesized and secreted during cellular activation; they are produced by different cells of the immune system and have multiple biological activities depending on the cell type to which they bind, for this reason they are defined as pleiotropic molecules; their biological functions can be redundant, as two different cytokines can have overlapping effects on the target cells; many cytokines can induce or inhibit the production of other cytokines by creating complex network of regulators that are able to finely modulate the biological effects; they may influence the activity of other cytokines, inducing antagonistic or synergistic effects.

They induce their biological effects by activating specific receptors on the cell surface and they can act on the same cells that secreted them (autocrine activity) or on neighboring cells (paracrine activity). In general, cytokines act mainly in the neighboring microenvironment in which they are produced; however, some cytokines (IL-1β and tumor necrosis factor α (TNFα)) may be present in the circulating blood and exert systemic and endocrine effects. Generally, the cellular responses to cytokines are expressed in several hours and require de novo production of mRNA and the synthesis of specific proteins. Cytokines play a critical role in cellular interactions and immune responses. These molecules exert many biological activities which ultimately coordinate multiple aspects of innate and acquired immunity as well as the control of the organs physiology. An important characteristic of cytokines is represented by their ability to regulate various aspects of the host immune response. The study of immunological characteristics of cytokines is complicated by the properties of pleiotropism, redundancy, regulation of the production of other cytokines, synergism, and antagonism. For examples, IL-1 is important for T-cell differentiation and at the same time together with TNFα is able to control the body temperature.

Most cytokines are not produced and do not act alone but they work as part of a complex network in which they regulate both the production activities of other cytokines and their effector activities. For this reason, their study is particularly complicated. The synergism is another important characteristic of certain cytokines. IL-2 and IL-12 act together in modulating the activity of cytotoxic lymphocytes (CTL) and the antagonism is another important characteristic of cytokine appearance. For example, the IL-10 produced by Th2 cells inhibits the activity of Th1 cells. Therefore, it is the overall balance between the different cytokines activities to determine the beginning, the maintenance, and the resolution of the immune and inflammatory responses.

It follows that the study of these mediators in vivo is extremely challenging since it is difficult to determine the exact sequence of events in which the cytokines are produced during the tissue interactions in which cells and mediators cooperate in the different phases of the inflammatory processes.

Cytokine Families

The number of known cytokines is wide and constantly expanding and therefore it is difficult to describe them all individually. However, the biological activity of cytokines is important in terms of molecular and cellular interactions between cells of the immune system and the parenchymal cells. Here, I summarize the main functional class of cytokines categorized based on the biological process they participate in. The key cytokines for each biological process will be described.

Proinflammatory Cytokines

Proinflammatory cytokines are produced by several cell types following interaction with microbes or from tissue-damaging events. These cytokines play a very important role as they are responsible for the activation of the innate and acquired immune response by enhancing the activity of immune system cells. These activities are mainly carried out by altering the expression of molecule important for the presentation of antigens such as Major Histocompatibility Complex (MHC) molecules and the costimulatory molecules such as CD80, CD86, and CD40. The cells most involved in these processes are the neutrophils, macrophages, dendritic cells (DCs) and mast cells. In general, proinflammatory cytokines possess pleiotropic functions in innate immunity. They orchestrate acute inflammatory processes locally and, in severe cases, systemically. In addition, they participate in shaping adaptive immunity by skewing the differentiation of naive helper T lymphocytes and by directly affecting the effector functions of different subsets of T and B lymphocytes.

The first cytokines to be produced in this class are IL-1β, IL-6, TNFα, and Interferons gamma (IFNγ). These cytokines are produced and act both on cells that produced them and on other cells of the immune system or the parenchyma.

IL-1α and IL-1β are ubiquitously expressed although monocytes/macrophages are the main producers. Both cytokines display an immune-stimulating and inflammatory activity and the mature form of the proteins as well as its extracellular release requires caspase-1 activity. Currently, IL-1β is considered the master regulator of the innate immunity. Different microbial ligands are able to induce the IL-1β gene either directly or indirectly through the secretion of other cytokines such as TNFα, IFNγ, or IL1 itself. IL-1β, IL-6, and TNFα participate to the induction of the acute phase response. Among different functions, IL-1β is able to induce other cytokines such as IL-6, adhesion molecules to promote cell–cell contact and transendothelial migration of inflammatory cells. IL1α and IL-1β exert similar effect by binding the same receptor complex, the IL1 type I and type II receptor. The IL1 receptors are present in different cells types.

IL-6 is a pleiotropic molecule produced by monocytes, endothelial cells, and from fibroblasts in response to IL-1β and TNFα. It is one of the major players in the induction of the acute phase response by stimulating hepatocytes to release plasmatic proteins important to fight bacterial infections. In addition, IL-6 induce B-cell differentiation and survival, T cells and thymocytes proliferation, and increase NK cell activity. IL-6 release is induced during inflammatory conditions upon stimulation of Toll-like receptors (TLRs) or upon stimulation of cells by IL-1β or TNFα. It binds to interleukin-6 receptor (IL-6R) which is not signaling competent on target cells; however, signaling is initiated upon association of the IL-6/IL-6R complex with a second receptor protein, the glycoprotein (gp) 130. gp130 dimerization leads to the activation of the tyrosine kinase Janus kinase 1 (JAK1).² An important characteristic of IL-6 is that it binds to its receptor gp130 only when the complex IL-6/IL-6R is formed. This has the consequence that whereas gp130 is expressed by all cells of the body, IL-6R expression is restricted to few cell types such as hepatocytes, some leukocytes, and some epithelial (e.g., biliary epithelial cells) and nonepithelial cells (e.g., hepatic stellate cells). Therefore, only IL-6R positive cells can respond to IL-6. Nevertheless, it has been shown that IL-6R can be cleaved by different proteases during a process called shedding³ and still being able to bind IL-6, broadening the spectrum of target cells. This IL-6 activity was defined IL-6 trans-signaling. As already mentioned, the major inducer of the hepatic acute phase proteins is IL-6 that is secreted by neutrophils, monocytes, and macrophages upon TLR stimulation.⁴ Activation of myeloid cells induces the release of IL-1β and TNFα that lead to a massive production of IL-6 from other cells. It is generally believed that while IL-6 classical signaling is crucial for the induction of the acute phase response, IL-6 trans-signaling mediates strong mitogenic signals for T, B cells and hepatocytes, function that it is particular important during liver regeneration. Nevertheless, it needs to be mentioned that there is a growing body of evidence that IL-6 maybe important for the control of metabolic functions.⁵ It has been observed that a correlation exists between serum levels of IL-6 and degree of obesity⁶ and the development of type 2 diabetes.⁷ These data show that in the liver, IL-6 not only regulates glucose metabolism but is also necessary to maintain tissue homeostasis for proper control of metabolic functions. The metabolic function of IL-6 should be further investigated also in other organs and indeed and future studies should consider that IL-6 classic and IL-6 trans-signaling might differentially regulate metabolism in a tissue-specific manner. In summary, IL-6 is a cytokine with pleiotropic functions. Under physiological conditions, it is essential for proper hepatic tissue homeostasis, liver regeneration, infection defense, and fine tuning of metabolic functions. However, persistent activation of the IL-6 pathway seems to be detrimental and can even lead to the development of liver cancer. Although much advancement has been made, there are still many open questions concerning the implication of IL-6 in physiology and pathology. In order to efficiently target only the detrimental effects of IL-6, we need to better understand the effects of IL-6 of different cell types of the liver and other organs.

TNF alpha (TNFα) is a key cytokine with a broad spectrum of biological activities with a key role in a variety of pathological processes. The biologically active native form of TNFα is a homotrimer. TNFα is produced by macrophages, DCs, B cells, and T cells as well as by other types of somatic cells such as endothelial cells, mast cells...