Terminology Origins and Nomenclature
At the dawn of immunology, researchers attempted to name factors based on their producer cells: lymphokines (products of lymphocytes) and monokines (products of monocytes). It soon became clear that there is no rigid link between molecules and specific cells, so a universal term was introduced — cytokines.
In 1979, at a symposium in Interlaken, the group name interleukins (IL) was proposed, reflecting their ability to mediate communication between leukocytes. Since then, all new molecules of this class (except chemokines) have been assigned the abbreviation IL and a sequential number (from IL-1 to IL-34 and beyond).
Historical names have been retained only for groups discovered earlier:
- Interferons (IFN) — responsible for antiviral defense.
- Colony-stimulating factors (CSF) — support the development of hematopoietic cells.
- Tumor necrosis factors (TNF) — cause necrosis of tumor cells.
- Chemokines — responsible for the directed movement (chemotaxis) of cells.
Structural Classification and Families
Since cytokines are extremely diverse, they are typically grouped based on their secondary structure:
- Predominantly $\alpha$-helical. They contain four helical domains. They can be short (such as IL-2 and IL-4) or long (such as IL-6 or IL-10).
- Predominantly β-sheet. These include the tumor necrosis factor family (forming a β-trefoil structure) and the IL-1 family (β-sandwich).
- Mixed structures (α/β). This group includes chemokines and mosaic molecules, such as IL-12.
For convenience, modern immunology more frequently uses classification by functional families. For example, Th1 cytokines induce inflammatory cellular immunity, Th2 cytokines promote humoral and antiparasitic immunity, and the IL-10 family is responsible for immunosuppression.
Genetics and Synthesis Kinetics
Cytokine genes are located on various chromosomes, but often form clusters as a result of evolutionary duplication. A striking example is the 5q23–33 segment on chromosome 5, which houses the genes for IL-3, IL-4, IL-5, IL-9, and IL-13.
The synthesis of the vast majority of cytokines is inducible. This means that an external stimulus is required for their production. The speed and nature of the response depend on the producer cell type:
- Myeloid cells (monocytes, macrophages): respond to bacterial products (LPS) via TLR receptors. The response is rapid: mRNA for IL-1β appears within 15 minutes, and peak synthesis is reached in 3–4 hours.
- Lymphoid cells (T helper cells): become activated upon antigen recognition by the TCR receptor. They act more slowly: IL-2 protein appears in 6–10 hours, with a peak reached by 24 hours.
The expression of inducible cytokines is always short-lived. This is ensured by strict regulatory mechanisms and the short half-life of their messenger RNA.
Cytokine receptors
Cytokines cannot affect a cell without binding to a specific receptor. Receptors are classified according to the structure of their polypeptide chains — this exact parameter determines which intracellular signaling machinery (tyrosine kinases, adaptor proteins) will be triggered.
There are three main receptor families:
- Hematopoietic. The largest group. Their extracellular domain contains the characteristic WSXWS sequence (tryptophan and serine residues).
- Interferon. Based on fibronectin family domains.
- TNFR family. Their extracellular domains are rich in cysteine residues.
Briefly: answers to topical questions
What intracellular signaling pathways are activated by cytokine receptors?
- Jak/STAT pathway (Jak/STAT) — the main signal transduction pathway for cytokine receptors: Jak kinases phosphorylate STAT, after which STAT proteins dimerize, translocate to the nucleus, and initiate target gene expression.
- Src family kinases (Src) — associate with cytokine receptors and participate in auxiliary signaling pathways.
- Phosphatidylinositol 3-kinase (PI3K) — associates with cytokine receptors and participates in auxiliary signaling pathways leading to the activation of AP-1 and other transcription factors.
- MAP cascade (MAP) — an auxiliary signaling pathway involved in signal transduction from IFNγ.
- Receptor pathways with intrinsic tyrosine kinase activity — involve phosphorylation of the receptor itself and adjacent molecules; kinase examples include c-Fms, c-Kit, and Flt-3.
Which specific cytokines are secreted by Th1 lymphocytes?
- Interferon gamma (IFNγ) — a key cytokine of Th1 cells.
- Interleukin-2 (IL-2).
- Tumor necrosis factor alpha (TNFα).
- Lymphotoxin alpha (TNFβ / lymphotoxin α).
- Interleukin-3 (IL-3) — a common cytokine for both Th1 and Th2 lineages.
- Granulocyte-macrophage colony-stimulating factor (GM-CSF) — a common cytokine for both Th1 and Th2 lineages.
Which cytokines belong to the Th2 profile?
- Interleukin-4 (IL-4).
- Interleukin-13 (IL-13).
- Interleukin-5 (IL-5).
- Interleukin-9 (IL-9).
- Interleukin-6 (IL-6).
- Interleukin-11 (IL-11).
- Interleukin-21 (IL-21).
- Interleukin-25 (IL-25).
- Interleukin-10 (IL-10).
- Interleukin-3 (IL-3) — a common cytokine.
- Granulocyte-macrophage colony-stimulating factor (GM-CSF) — a common cytokine.
Which cytokines can be expressed in a membrane-bound form?
- Interleukin-1 alpha (IL-1α) — a human cytokine found predominantly in a membrane-associated form.
- TNF family (TNF) — an entire family for which the membrane form is more characteristic than the secreted form.
- Tumor necrosis factor alpha (TNFα) — synthesized as a functionally active membrane-bound precursor molecule.
- Interleukin-15 (IL-15) is a protein that can exist in a membrane-bound form.
- BAFF and APRIL (BAFF, APRIL) are members of the TNF family that have a membrane-associated form.
Which specific molecules belong to the chemokine group?
- CXCL8 (IL-8 / CXCL8) is a molecule containing an α-helix and β-sheets.
- CXCL12, CXCL13 (CXCL12, CXCL13) are homeostatic chemokines.
- CCL1, CCL2, CCL7, CCL8, CCL11, CCL12, CCL13, CCL17, CCL19, CCL20, CCL21, CCL22, CCL24, CCL25, CCL26, CCL27, CCL28 (CCL chemokines) are representatives of the CC-chemokine group.
- Fractalkine (CX3CL1) is the sole representative of CX3C chemokines.
- XCL1, XCL2 (XCL1, XCL2) are γ-chemokines.
To remember chromosome 5, which houses a large cluster of cytokine genes, recall the consecutive numbers: IL-3, IL-4, IL-5 — all of them are encoded on chromosome 5.
Class and exam questions
What is the difference between cytokines and growth factors?
Epidermal, fibroblast, and platelet-derived growth factors are not cytokines. The only exception is transforming growth factor beta (TGFβ), which is classified as a cytokine due to its involvement in immune system regulation.
Are there any cytokines that are not secreted extracellularly by the cell?
Yes, membrane-bound forms do exist. For example, in humans, this is characteristic of IL-1α, whereas for the entire tumor necrosis factor (TNF) family, the membrane form is even more typical than the soluble one.
What triggers a cell to start producing cytokines?
A cell initiates synthesis only after stimulation of the corresponding receptors by natural ligands. For macrophages, these are bacterial components (e.g., LPS) acting via pattern recognition receptors (PRRs/TLRs), while for T lymphocytes, they are antigens stimulating the antigen-recognition receptor (TCR).
What else to study on this topic
- Detailed characterization of individual interleukins (from IL-1 to IL-34: molecular weights, targets, receptors).
- Specifics of membrane-bound forms in the tumor necrosis factor (TNF) family.
- Mechanisms of signal transduction from cytokine receptors: kinases and transcription factors.
- Chemokines: classification (CC, CXC, C) and their role in leukocyte migration.
- Features of homeostatic cytokine expression in embryogenesis and thymic tissues.
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