Cytokines: Definition, Attributes, Function, Production, Types and Clinical Uses

They are a large group of proteins, peptides, or glycoproteins that are secreted by specific cells of the immune system.

Cytokines are a category of signaling molecules that mediate and regulate immunity, inflammation, and hematopoiesis.

Cytokines are produced throughout the body by cells of diverse embryological origin.

The term cytokine is a general name; other names are defined according to their presumed function, secretory cell, or target of action.

For example, cytokines produced by lymphocytes can also be called lymphokines.

Many of the lymphokines are also known as interleukins (IL), as they are not only secreted by leukocytes but can also affect the cellular responses of leukocytes.

Cotiquines or cytokines secreted by monocytes or macrophages are called monokines. And chemokines are cytokines with chemotactic activities.

Cytokines and their receptors show a very high affinity for each other. Due to this high affinity, picomolar concentrations of cytokines can mediate a biological effect.

A particular cytokine can exhibit:

  • Autocrine action by binding to the receptor on the membrane of the same cell that secreted it.
  • Paracrine action binds to receptors on a target cell near the producer cell.

Endocrine activity travels through the circulation and acts on target cells in distant parts of the body.

Attributes of cytokines

Cytokines can regulate cellular activity in a coordinated interactive manner due to the following attributes:

  • Pleiotrophy – A cytokine has many different functions.
  • Redundancy – Several different cytokines can mediate the same or similar functions.
  • Synergism : occurs when the combined effect of two cytokines on cell activity is greater than the additive effects of individual cytokines.
  • Antagonism : the effects of one cytokine inhibit or offset the effects of another cytokine.

Cytokine families

Several cells in the body make a large family of cytokines.

Also the cytokine superfamily includes interleukins, chemokines, colony stimulating factors (CSF), interferons and transforming factors (TNF) and families of tumor necrosis factor (TGF).

Cytokines exist in broad families that are structurally related but can contain quite diverse cytokine functions.

Cytokine families share sequence similarities and exhibit homology and some promiscuity in their reciprocal receptor systems. They do not exhibit functional similarity.

Cytokine families also contain important membrane regulatory and cell membrane receptor pairs.

This reflects the evolutionary pressures that use common structural motifs in various immune functions in higher mammals.

The TNF / TNF receptor superfamily contains immunoregulatory cytokines, including TNF-α; lymphotoxins.

And also cellular ligands, such as CD40L, which mediates B and T cell activation, and FasL (CD95), which promotes apoptosis.

Similarly, the IL-1 / IL-1 receptor superfamily contains cytokines, which include IL-1 β, IL-1 α, IL receptor antagonist, IL-18, and IL-33.

These are the ones that mediate the physiological and defense function of the host, but this family also includes Toll-like receptors, a series of mammalian pattern recognition molecules.

Receptors play a crucial role in the recognition of microbial species early on in innate responses.

Cytokine production

Cytokines are synthesized in the Golgi and can transit through the endoplasmic reticulum to be released as soluble mediators.

They can also remain membrane bound, or they can be processed into cytosolic forms that can transit intracellularly even returning to the nucleus.

In the nucleus they can act as transcriptional regulators.

Numerous factors promote cytokine expression in vivo, including:

  • Cell-cell contact.
  • Immune complexes / autoantibodies.
  • Activation of the local plugin.
  • Microbial species and their soluble products.
  • Reactive oxygen and nitrogen intermediates.
  • Trauma.
  • Total stress.
  • Ischemia.
  • Radiation.
  • Ultraviolet light.

Cytokine receptor

Cytokine receptor family, signaling and therapeutic treatment of diseases.

Cytokines act on their target cells by binding to specific membrane receptors. Many cellular functions are regulated by members of the cytokine receptor superfamily.

Cytokine receptor signaling is dependent on their association with Janus kinases (JAKs) that link ligand binding to tyrosine phosphorylation of recruited signaling proteins for the cytokine receptor complex.

Among these signaling proteins are a unique family of transcription factors called signal transducers and activators of transcription (STAT).

The receptors and their corresponding cytokines have been divided into several families based on their structure and activities, including:

  • Type I cytokine receptors.
  • Type II cytokine receptors.
  • Chemokine receptors.
  • Tumor Necrosis Factor Receptor Superfamily (TNFR).
  • TGF-beta receptors.
  • Immunoglobulin (Ig) superfamily.

Cytokine therapy

The therapy has been taken as a natural alternative to control the disease.

Disease control in food production animals is normally mediated by the use of vaccines, chemicals, and antibiotics.

However, the extensive use of antibiotics and chemicals in livestock has resulted in problems for human and environmental health, particularly with regard to the emergence of drug-resistant bacteria in the food chain.

In fact, the World Health Organization (WHO) has urged meat producers to use environmentally friendly alternative methods to control disease.

Cytokines, as natural mediators of the immune response, offer interesting alternatives to conventional therapies.

The use of cytokines is becoming more and more feasible with the recent cloning of several cytokine genes.

Cytokine therapy has proven to be a novel therapeutic approach in the treatment of patients with advanced malignancies.

The purpose of this type of therapy is to manipulate the immune response in such a way that it generates the appropriate immune effector cells to eradicate solid tumors.

Cytokine therapy is given only after conventional therapies, such as chemotherapy, radiation therapy, and surgery, have been done.

Various cytokine administration regimens have been implemented to eradicate solid tumors in patients with melanoma and renal cell cancer.

Clinical trials have been conducted involving the administration of interferon gamma, interferon alpha, interleukin 2, tumor necrosis factor alpha, and interleukin 12.

Advances in cytokine therapy have been thwarted by the relatively high level of toxicity associated with the administration of cytokines.

The maximum tolerated dose of the cytokine is designated as the above dose. In turn, determining the treatment schedule is another challenge for clinicians.

Partial or complete tumor regression has been observed in some clinical trials, offering hope of finding the appropriate cytokine or combination of cytokines and the dose level to effectively treat advanced malignancies.

In this way it can be less toxic to the patient.

Common toxicities include:

  • Sickness.
  • Vomiting
  • Fever / chills
  • Fatigue.
  • Headache.

Dose escalation of a particular cytokine stops once three patients at a particular dose level experience grade three toxicity. The maximum tolerated dose of the cytokine is designated as the above dose.

In turn, determining the treatment schedule is another challenge for clinicians.

Partial or complete regression of the tumor has been observed in some clinical trials, offering hope of finding the right cytokine or combination of cytokines.

Advances in understanding the role of cytokines in immune and inflammatory disorders have led to the development of cytokine-based therapies.

Therapies have been developed with the express goal of blocking / inhibiting or restoring the activity of specific cytokines.

Cytokines delivered by gene therapy and antisense oligonucleotide treatment are also being evaluated.

Currently, the most widely used approach to cytokine therapy is to block or neutralize the action of cytokines with monoclonal antibodies (mAbs).

Drugs that block inflammatory cytokines, such as tumor necrosis factor (TNF) -, are among the most successful therapies approved for clinical use.

Immunotherapy with cytokines

Immunotherapy is a medical term defined as “treating disease by inducing, enhancing, or suppressing an immune response.”

The active agents of immunotherapy are collectively referred to as immunomodulators.

They are a variety of natural and synthetic recombinant preparations, often cytokines, such as granulocyte colony stimulating factor (G-CSF), interferons, imiquimod, and fractions of the cell membrane of bacteria that are already licensed for use in patients. .

Other studies including IL-2, IL-7, IL-12, various chemokines, synthetic cytosine phosphate-guanosine (CpG), oligodeoxynucleotides, and glucans are being extensively investigated in preclinical and clinical studies.

Types of cytokines

Cytokines are a broad and loose category of small proteins (~ 5–20 kDa) that are important in cell signaling.

They are released by cells and affect the behavior of other cells, and sometimes the releasing cell itself.

There are many types of cytokines, including chemokines, interferons, interleukins, lymphokines, tumor necrosis factor, but they are generally not hormones or growth factors (despite some terminology overlaps).

All of these types of cytokines are produced by a wide range of cells, including immune cells such as macrophages, B lymphocytes, T lymphocytes, and mast cells, as well as endothelial cells, fibroblasts, and various stromal cells.

A given cytokine can be produced by more than one type of cell.

Inflammatory cytokines

Inflammation is mediated by a variety of soluble factors, including a group of secreted polypeptides known as cytokines.

Inflammatory cytokines can be divided into two groups: those involved in acute inflammation and those responsible.

Inflammation, the tissue response to injury, is characterized in the acute phase by increased blood flow and vascular permeability, along with the accumulation of fluids, leukocytes, and inflammatory mediators such as cytokines.

Several cytokines play a key role in mediating acute inflammatory reactions, namely IL-1, TNF-α, IL-6, IL-11, IL-8 and other chemokines, G-CSF and GM-CSF.

Cytokines that are known to mediate chronic inflammatory processes can be divided into those that participate in humoral inflammation.

Estas son IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, IL- 13, y el factor de crecimiento transformante b (TGF-b), y aquellos que contribyen to the inflamación celular como IL-1, IL-2, IL-3, IL-4, IL-7, IL-9, IL-10, IL-12, interferones (IFN), factor inductor de IFN-g ( IGIF), TGF-b, y TNF-a y -b.

Inflammatory abnormalities are a large group of disorders that underlie a wide variety of human diseases.

Cytokines are regulators of host responses to infection, immune responses, inflammation, and trauma.

Some cytokines work to worsen disease (pro-inflammatory cytokines), while others work to reduce inflammation and promote healing (anti-inflammatory cytokines).

Proinflammatory cytokines

A pro-inflammatory cytokine is a cytokine that promotes systemic inflammation.

Examples include IL-1 and TNF alpha. Interleukin (IL) -1 and tumor necrosis factor (TNF) are pro-inflammatory cytokines, and when administered to humans, they cause fever, inflammation, tissue destruction, and, in some cases, shock and death.

The reduction of the biological activities of IL-1 and TNF is accomplished by several different, but very specific strategies.

Thus they include neutralizing antibodies, soluble receptors, receptor antagonists, and protease inhibitors that convert inactive precursors into active, mature molecules.

Blocking IL-1 or TNF has been highly successful in patients with rheumatoid arthritis, inflammatory bowel disease, or graft-versus-host disease, but has clearly not been successful in humans with sepsis.

Agents such as TNF-neutralizing antibodies, soluble TNF receptors, and IL-1 receptor antagonist have been infused into more than 10,000 patients in double-blind, placebo-controlled trials.

Although there has been a highly consistent small increase (2-3%) in 28-day survival rates with antitokine treatment, the effect has not been statistically significant.

Anti-inflammatory cytokines

Anti-inflammatory cytokines are a series of immunoregulatory molecules that control the response of pro-inflammatory cytokines.

Cytokines act in concert with specific cytokine inhibitors and soluble cytokine receptors to regulate the human immune response.

Its physiological role in inflammation and pathological role in systemic inflammatory states are increasingly recognized. The major anti-inflammatory cytokines include the interleukin (IL) -1 receptor antagonist, IL-4, IL-6, IL-10, IL-11, and IL-13.

Specific cytokine receptors for IL-1, tumor necrosis factor alpha, and IL-18 also function as pro-inflammatory cytokine inhibitors.

Role of cytokines

Cytokines are small glycoproteins produced by various types of cells, predominantly leukocytes, that regulate immunity, inflammation, and hematopoiesis.

They regulate a number of physiological and pathological functions including innate immunity, acquired immunity, and a host of inflammatory responses.

The discovery of cytokines began in the 1950s, but the precise identification of their structure and function took many years. The original discoveries were those of IL-I, IFN, and nerve growth factors (NGF).

However, these cytokines were purified and received their names years later.

The elucidation of the precise physiological, pathological and pharmacological effects of some of the cytokines is still in progress.

Modern molecular biology techniques were primarily responsible for their complete identification, and as a consequence, several hundred cytokine proteins and genes were identified, and the process continues.

Cytokines are produced from various sources during the effector phases of natural and acquired immune responses and regulate immune and inflammatory responses.

They are also secreted during non-immune events and play a role unrelated to the immune response in many tissues. In general, its discharge is a brief, self-limited event.

They are not only produced by multiple types of cells, but they also act on different types of cells and tissues.

Cytokines often have multiple effects on the same target cell and can induce or inhibit the synthesis and effects of other cytokines.

After binding to specific receptors on the cell surface of target cells, cytokines produce their specific effects. Multiple signals regulate the expression of cytokine receptors.

Target cells respond to cytokines by new mRNA and protein synthesis, resulting in a specific biological response.

They act through receptors, and are especially important in the immune system.

Cytokines modulate the balance between humoral and cell-based immune responses, and regulate the maturation, growth, and responsiveness of particular cell populations.

Some cytokines enhance or inhibit the action of other cytokines in complex ways, resulting in a specific biological response.

They act through receptors, and are especially important in the immune system.