CYTOKINES: FUNCTIONS, TYPES AND RECEPTORS - BIOLOGY - 2025

The cytokine or cytokines are small signaling proteins (some authors refer to these as peptides) that regulate many biological functions, many of them related to the immune system, hematopoiesis, tissue repair and cellular proliferation.

The term "cytokine" groups together a large number of proteins that have vastly different structural and functional characteristics, and means, more or less, "factors produced by cells", since their synthesis is not restricted to a single type of cell in the body.

Ciokine release process (Source: www.scientificaimations.com / CC BY-SA (https://creativecommons.org/licenses/by-sa/4.0) via Wikimedia Commons)

These proteins are produced and secreted in high concentrations by different types of cells in animals and can affect nearby cells, which is why they are said to exert "paracrine" signaling functions.

They can also act remotely by inducing the secretion of soluble factors into the bloodstream (endocrine or systemic function) and can even act directly on the cell that synthesizes them (autocrine function).

Cytokines are seen as "symbols" of a specialized language, whose meaning depends on the context in which they are expressed and sent from one place to another.

The first cytokines described were lymphokines, soluble products produced by lymphocytes in response to polyclonal and specific antigens; these represent an important group of immune response factors.

Cytokine functions

Cytokines are soluble glycoproteins (not immunoglobulins) of small size (up to 40 kDa) that are produced and released by different types of cells in the body, they can have local or remote actions, which they exert in peak or nanomolar concentrations.

Communication in the immune system

The most notable function of cytokines is their participation in communication between the various components of the immune system and the exchange of information between these components and the other cells of the body (intercellular signaling).

In other words, virtually all immune functions depend on the biological activity of these systemic "messengers."

Cytokines exhibit a wide range of immunological functions, both effector and regulatory, and their effects at the level of tissues and biological systems, in most of the organisms where they are produced, can be extremely extensive and complex.

They are such important immunological effectors that the type of cytokine produced during the immune response to any stimulus initially determines whether the response will be cytotoxic, humoral, cellular, or allergic.

Defense against viruses

They are deeply involved in inflammatory processes and in defense against infections of viral origin; they participate in the presentation of antigens, in the differentiation of the bone marrow, in the activation and recruitment of cells, in the expression of cell adhesion molecules, etc.

Thus, cytokines not only participate in the body's immune defense, but also in "normal", physiological and metabolic processes, thereby integrating both aspects of cellular and organic life.

Growth factors

Many authors consider that these proteins behave as growth factors, since representatives such as tumor necrosis factor (TNF), lymphokines, interleukins and interferons (IFNs) are actively related to cell proliferation, death, differentiation and development in different body contexts.

This video shows an animation in which a macrophage ingests bacteria and later releases cytokines:

Cytokines and hormones?

Various scientists make an analogy between cytokines and hormones, but this is not entirely correct for some important reasons:

- Hormones are synthesized and released by fairly specialized tissues, while cytokines are produced by a large number of different cells in the body.

- Hormones are the primary synthetic product of the specialized cells that produce them, while cytokines represent only a small amount of the products synthesized by a cell.

- The expression of the hormones occurs in response to homeostatic control signals (some of which depend on the circadian cycle), but cytokines, on the other hand, are only expressed when they are specifically stimulated by events "harmful" to cell life.

Types of cytokines

Many cytokines were initially described according to their main biological functions, but today they are characterized mainly by their structure, as they can exert a great diversity of functions that are difficult to summarize in a short epithet.

However, the current classification of these proteins depends on several parameters: some have been identified according to the "numerical order" of their discovery, according to some functional activity, according to their participation in inflammatory responses, according to its primary cellular origin and according to its structural similarity with other related molecules.

Thus, members of a "superfamily" of cytokines share characteristics such as sequence homologies, reciprocal receptor systems, etc., although not necessarily structural similarity. Some families are known:

- The TNF family - TNF Receptors (Tumor Necrosis Factor), which includes immunoregulatory cytokines such as tumor necrosis factor (TNF), lymphotoxins and some cellular ligands such as CD40L (mediates the activation of B and T lymphocytes) and FasL or CD95 (promotes programmed cell death).

- The IL-1 / IL-1 Receptor (Interleukin) family, a group where the cytokines IL-1β, IL-1α, IL-18, IL-33 and IL-36 are classified, as well as receptor antagonists, known as IL-1RA, IL-38 and the anti-inflammatory cytokine IL-37 (mediates physiological and defense functions).

- The IL-1 / IL-1 Receptor family also includes Toll-like receptors (TLRs), which act as molecules of the innate immune system for the recognition of molecular patterns associated with species microbial.

Certain texts of related scientific literature group cytokines according to their production site into "mononuclear phagocyte derived cytokines" and "T lymphocyte derived cytokines". They also separate them in relation to the responses they mediate: cytotoxic (antiviral and anti-cancer), humoral, cellular, or allergic; in addition to those that are immunosuppressive.

- According to the inflammatory response

Depending on whether or not they promote inflammatory reactions or responses, cytokines are classified into pro-inflammatory cytokines and anti-inflammatory cytokines.

Pro-inflammatory cytokines

Inflammation mediated by these cytokines consists of a cascade of expression of gene products that are not usually expressed in a healthy human.

Although certain endotoxins and other “inflammatory” products are capable of triggering the expression of these “pro-inflammatory” genes, the cytokines IL-1 and TNF, and even IFN-γ interferon, are particularly effective in their stimulation, therefore which are said to be the main pro-inflammatory cytokines.

Structure of the human beta inferteron (Source: via Wikimedia Commons)

Regardless of whether the inflammatory process was triggered by infection, trauma, ischemia, activated T cells, or some toxin, these two molecules act synergistically to initiate the cascade of inflammatory mediators.

Anti-inflammatory cytokines

These proteins, on the contrary, block the inflammatory response process or suppress the intensity with which it occurs. Part of this group are the interleukins IL-4, IL-10, IL-13, and transforming growth factor (TGF) -β (which blocks the production of IL-1 and TNF).

There is also IL-6 - produced by B cells, T cells and monocytes - and IL-11 - produced by stromal cells and fibroblasts.

Based on the above, it is said that the development of a disease (either in the short or long term) depends, to a large extent, on the “balance” between the effects of pro-inflammatory and anti-inflammatory cytokines.

In fact, some research suggests that susceptibility to certain diseases is genetically determined by the balance in the expression of the genes encoding the two types of cytokines.

A pathological condition progresses, then, when anti-inflammatory mediators provide a control that is not sufficient to block pro-inflammatory activity (in diseases controlled by the immune system) or when control is exaggerated and ends up inhibiting the immune response, causing the host to have the risk of a systemic infection.

Receivers

An essential part of the function of any cytokine is its interaction and association with a receptor pair (ligand-receptor interaction).

Some authors classify cytokines according to the type of receptor to which they bind, which can be:

- Type I (of the hematopoietin family)

- Type II (of the interferon family)

- The family of receptors of TNF proteins (tumor necrosis factor)

- IL-1 receptors

- Toll type receptors

- IL-17 receptors

- Tyrosine kinase receptors

- Family of transforming growth factor receptor serine kinases

Type I (of the hematopoietin family)

Hormones (erythropoietin (EPO), thrombopoietin (TPO) and leptin), and cytokines such as granulocyte colony stimulating factors (G-CSFs), the stimulating agents of macrophage granulocyte colonies (GM-CSFs) and the interleukins IL-2 to IL-7, IL-9, IL-11 to IL-13, IL-15, IL-21, IL-23, IL-27, IL- 31 and IL-35.

These "type I" cytokines are characterized by the similarity they share in their sequences, as each contains four antiparallel alpha helices with two connections or loops, one short and one long, which are structurally "arranged" in an "up-up configuration. ”And“ down-down ”.

Type II (from the interferon family)

These receptors are bound by interferon IFN-α / β, IFN-γ, interleukins IL-10, IL-19, IL-20, IL-22, IL-24, IL-26 and IL-28 to IL- 30.

They are heterodimers composed of two subunits known as IFNAR1 and IFNAR2, which share similarity with some motif sequences in type I receptors. They work mainly with antiviral cytokines.

IL-1 and Toll-like receptors (TLR)

They are associated with responses triggered by interleukin IL-1α / β, IL-18, IL-33, and IL-36 to IL-38.

Transforming growth factor receptor serine kinase family

This family of cytokine receptors is related to the response of the proteins TGF-β1, TGF-β2, and TGF-β3, which are produced by T cells, macrophages, and other cells in the body.

References

1. Borish, LC, & Steinke, JW (2003). 2. Cytokines and chemokines. Journal of Allergy and Clinical Immunology, 111 (2), S460-S475.
2. Cavaillon, JM (1994). Cytokines and macrophages. Biomedicine & pharmacotherapy, 48 (10), 445-453.
3. Dinarello, CA (2000). Proinflammatory cytokines. Chest, 118 (2), 503-508.
4. Nathan, C., & Sporn, M. (1991). Cytokines in context. The Journal of cell biology, 113 (5), 981-986.
5. Opal, SM, & DePalo, VA (2000). Anti-inflammatory cytokines. Chest, 117 (4), 1162-1172.
6. O'Shea, JJ, Gadina, M., & Siegel, RM (2019). Cytokines and cytokine receptors. In Clinical immunology (pp. 127-155). Content Repository Only !.