Textbook - BIOLOGICAL CHEMISTRY - Hubsky Y.I. - 2000

Chapter VI. BIOCHEMISTRY OF PHYSIOLOGICAL FUNCTIONS AND SPECIALIZED TISSUES

CHAPTER 30. BIOCHEMISTRY OF IMMUNE PROCESSES

30.3. MEDIATORS AND HORMONES OF THE IMMUNE SYSTEM

There is a significant number of physiologically active compounds synthesized in The Immune System that act as intercellular chemical signals, regulating its activity and mediating Intercellular Communication. These substances are collectively known as cytokines or lymphokines.

Cytokines are produced by activated lymphocytes and other immunocompetent Cells, controlling the processes of maturation, functioning, and interaction between lymphocytes and other cellular effectors of Immunity. Specific targets for lymphokines are lymphocytes and macrophages that bear sensitive receptors on their surfaces. Lymphokines are secreted by macrophages, leukocytes, and other Blood and Connective Tissue cells involved in immune responses and the body's nonspecific resistance during inflammation.

The Thymus also performs a hormonal intra-systemic function by secreting BIOLOGICALLY ACTIVE SUBSTANCES (thymosins, thymopoietins, thymostimulins, etc.) that ensure the maturation of T-lymphocytes.

By their chemical nature, the mediators and Hormones of the immune system are Proteins, Glycoproteins, and low- or high-molecular-weight Peptides present in human Blood Plasma, which exert their regulatory Functions at picomolar (10¹²) concentrations. A significant number of substances functioning as lymphokines remain insufficiently characterized as individual chemical compounds to this day.

Main Classes of Cytokines

Interleukins (IL) are growth factors of the immune system: proteins produced by T-lymphocytes and macrophages that stimulate the proliferation of lymphocytes and certain other Cells of the body. Currently, more than ten distinct types of interleukins have been isolated (IL-1 — IL-16), which differ in Structure, physicochemical properties, and spectrum of biological activity.

Interleukin-1, or lymphocyte-activating factor, is a mediator produced by stimulated macrophages, as well as polymorphonuclear leukocytes, Skin epithelial cells, and transformed cells from patients with monocytic leukemia. The main effect of IL-1 action is The stimulation of T-helper proliferation and the induction of interleukin-2 secretion by T-helpers. IL-1 is also an activator of inflammation as a protective response of the body. This function of IL-1 is associated with its ability to induce the expression of phospholipase A₂ and cyclooxygenase genes, which is a biochemical prerequisite for the stimulated synthesis of Prostaglandins and Leukotrienes in sites of inflammation; in addition, the interleukin stimulates fibroblast proliferation, the synthesis of "acute-phase proteins of inflammation" in hepatocytes, and collagenase in the synovial membranes of joints.

Two Types of interleukins-1 have been characterized in The Human Body, which are proteins consisting of 159 (IL-1α) and 153 (IL-1β) amino acid residues. The Molecular Weight of interleukins-1 is 12 kD.

Interleukin-2 is a factor produced by mature T-helpers As a result of their stimulation by an antigen. IL-2 occupies a central place in the interleukin regulation system of immunity, enhancing the processes of both cellular and humoral immunity. Under METABOLISM/18.html">The Influence of IL-2, T-lymphocytes differentiate into T-killers, which destroy tumor and microbe-infected cells, and The production of γ-interferon by T- and NK-cells is activated. Interleukin-2 is a glycoprotein containing sialic acid residues; the molecular weight of human IL-2 is about 13.5 kD.

Interleukin-3, or colony-stimulating factor (CSF), is synthesized by activated T-helpers. The main target of IL-3 biological action is hematopoietic stem cells—precursors of lymphocytes—whose growth this interleukin stimulates. By its chemical nature, interleukin-3 is a glycoprotein consisting of 134 amino acid residues.

Interferons are protein factors synthesized by lymphocytes and other animal cells upon interaction with Viruses. Interferons are universal antiviral agents active against any viruses, yet they exhibit species Specificity, meaning that each animal species possesses its own Class of interferons.

There are Three types of interferons produced by various cells, designated as IFN-α, IFN-beta, and IFN-γ. IFN-α is synthesized primarily by Blood Leukocytes ("leukocyte interferons"), IFN-beta by fibroblasts ("fibroblast interferons"), and IFN-γ by T- and B-lymphocytes ("immune interferons").

The molecular weight of various interferons ranges from 16 to 20-25 kD. IFN-α and IFN-beta are single-chain peptides consisting of 166 amino acid residues; IFN-γ contains 143 amino acid residues. Type α interferons have non-glycosylated peptide chains, whereas types beta and γ are glycoproteins. The genes encoding IFN-α and IFN-beta are localized on the 10th chromosome of the Human Karyotype, and the IFN-γ Gene is on the 12th chromosome.

Upon interacting with cells infected by Viral Particles, interferons inhibit the synthesis of viral proteins, which leads to the blockage of viral Replication in the infected Cell.

MOLECULAR MECHANISMS OF the Antiviral Action of Interferons

1. Binding of interferons to target cell receptors. Interferons secreted into the extracellular environment by producer cells interact with specific receptors on the membranes of sensitive cells, which is a prerequisite for chemical signal generation and its transmembrane transmission.

2. Activation of intracellular 2',5'-oligoadenylate synthetase. The chemical signal reaches The Genome of the virus-infected cell via intracellular messengers and induces the synthesis of an enzyme that forms 2',5'-oligoadenylic acid from ATP molecules (2'5'-oligo-A-synthetase). 2',5'-Oligoadenylate is an activator of RNase I, which cleaves single-stranded viral RNAs (mRNAs) and Ribosomal RNAs necessary for the Translation of viral proteins.

3. Activation of intracellular protein Kinases. The transmembrane chemical signal generated by interferon also causes the Activation of a protein kinase that phosphorylates the Translation initiation factor IF-2. Phosphorylation of initiation factor IF-2 leads to its inactivation and blocks the ribosomal synthesis of viral proteins.

Tumor Necrosis Factors (TNF). TNF-α and TNF-beta are distinguished.

TNF-α (cachectin) is a protein with a molecular weight of 17 kD, produced by monocytes and macrophages. Its main biological effects are the induction of IL-1 and IFN-γ synthesis, as well as cytotoxic and cytostatic action.

TNF-beta (lymphotoxin) is a protein with a molecular weight of 25 kD, produced by T-lymphocytes, causing a cytotoxic effect.

When introduced into the body, TNF induces lysis in certain types of human tumor cells, making them promising candidates for anticancer therapy.

Colony-stimulating factors (CSFs) are cytokines that stimulate the growth of hematopoietic cells (granulocytes, monocytes, and erythroid progenitor cells). They are produced by T lymphocytes, macrophages, monocytes, and endothelial cells (cf. IL-3).

Transforming growth factors (TGFs) are proteins produced by various classes of lymphocytes, platelets, the Placenta, and certain tumors. They stimulate fibroblast proliferation, Collagen and Fibronectin synthesis, and play a key role in angiogenesis and wound healing. At the same time, TGFs suppress the proliferation of T AND B lymphocytes, as well as The activity of cytotoxic and killer cells.

It is worth noting that activated lymphocytes and other immunocompetent cells synthesize peptide growth factors—such as epidermal growth factor (EGF) and nerve growth factor (NGF)—as well as somatomedins (Insulin-like Growth Factors IGF-1 and IGF-2) and various protein-polypeptide hormones. This highlights the crucial role of the immune system in regulating growth, proliferation, and Cell Differentiation.