The Science of Cytokines: Bridging Immunity, Inflammation, and Healing

Cytokines are a class of small, bioactive proteins with extensive biological functions. They play a crucial role in regulating both innate and adaptive immunity and are involved in hematopoiesis, cell growth, and tissue repair following injury. In this edition of the Cell Biology Academy, we will provide a comprehensive overview of cytokine classifications and functions to support you in efficiently initiating your experiments.

Cytokines: Key Drivers of Immunity and Disease

Cytokines are a group of soluble peptides or proteins secreted by various cells, both immune and non-immune. These molecules mediate intercellular communication by interacting with their specific receptors to regulate cellular proliferation, differentiation, and apoptosis, as well as to induce immune responses [1]. Cytokines exert their signaling functions through paracrine, autocrine, and endocrine mechanisms [2].

Initially, cytokines were isolated from human serum and animal tissues. With advancements in genetic engineering technology, researchers began extracting cytokines using genetically engineered Escherichia coli systems. Today, commonly used expression systems for cytokines also include mammalian cells (e.g., CHO, HEK293), yeast (Pichia pastoris, Saccharomyces cerevisiae), and insect cells (e.g., SF9, SF21).

In scientific research, cytokines are typically recombinant—bioactive proteins produced through expression systems, rather than being directly produced by stimulated cells.

Classification and Functions of Cytokines

Cytokines can be classified into six categories:

A.Interleukins (IL) – Involved in the regulation of immune cell activation, differentiation, and proliferation.

B.Colony-Stimulating Factors (CSFs) – Stimulate the production and differentiation of hematopoietic cells.

C.Interferons (IFNs) – Play key roles in antiviral responses, immune modulation, and tumor suppression.

D.Growth Factors – Regulate cell growth, proliferation, and tissue repair.

E.Chemokines – Mediate chemotaxis, directing the migration of immune cells to sites of inflammation or injury.

F.Tumor Necrosis Factors (TNFs) – Involved in inflammation, apoptosis, and immune regulation, particularly in the response to cancerous cells and infections.

1. Interleukins (IL)

The term interleukin was first introduced at the Second International Lymphokine Conference held in Interlaken, Switzerland, in 1979. The conference standardized the nomenclature for cytokines that are produced and secreted by leukocytes and mediate interactions among leukocytes. These cytokines were collectively named interleukins and differentiated by Arabic numerals.

As of 2023, 38 distinct interleukins have been identified and classified.

Interleukins Overview

2. Colony-Stimulating Factors (CSFs)

Colony-stimulating factors (CSFs) are cytokines that stimulate the proliferation and differentiation of multipotent hematopoietic stem cells and hematopoietic progenitor cells at various stages of development.

Colony-Stimulating Factors Overview

3. Interferons (IFNs)

Interferons (IFNs) are a class of glycoproteins primarily involved in antiviral defense, inhibition of cell proliferation, immune modulation, and anti-tumor activity.

Interferons Overview

4. Growth Factors

Growth factors are a group of polypeptides that influence the growth, differentiation, apoptosis, and immune regulation of various cells.

Common Growth Factors and Their Functions

A.Platelet-Derived Growth Factor (PDGF): Promotes the division and proliferation of vascular smooth muscle cells, fibroblasts, and mesothelial cells.

B.Fibroblast Growth Factor (FGF): Stimulates the proliferation and differentiation of fibroblasts, mesothelial cells, and vascular endothelial cells.

C.Hepatocyte Growth Factor (HGF): Enhances the division and proliferation of hepatocytes, involved in liver cell repair and regeneration.

D.Epidermal Growth Factor (EGF): Stimulates the proliferation and differentiation of epidermal cells, accelerates skin wound healing.

E.Vascular Endothelial Growth Factor (VEGF): Promotes the proliferation and migration of vascular endothelial cells, increases vascular permeability, and is involved in tumorigenesis and development.

F.Nerve Growth Factor (NGF): Stimulates the proliferation, differentiation, and survival of nerve cells, involved in nerve regeneration and repair.

G.Insulin-like Growth Factor (IGF): Promotes cell proliferation, differentiation, and secretion, facilitates glucose metabolism and glucose transport in adipose tissue, and enhances the synthesis of fats and glycogen.

5. Chemokines

Chemokines are a class of structurally similar small molecule secreted proteins that activate corresponding G-protein-coupled receptors to initiate intracellular signaling pathways. They are involved in processes such as cell migration, proliferation, and inflammation, playing critical roles in both physiological and pathological conditions [3].

Chemokines comprise over 50 members and are classified into four groups based on their structure: CC, CXC, CX3C, and XC. Corresponding chemokine receptors are categorized into CCR, CXCR, CX3CR, and XCR, with approximately 20 members.

An important function of chemokines is to regulate leukocyte infiltration in inflammatory and immune diseases by establishing a concentration gradient [4]. Chemokines are also involved in various physiological processes, such as angiogenesis and neuronal development, as well as pathological conditions, including neurodegenerative and neuropsychiatric diseases.

6. Tumor Necrosis Factor (TNF)

Tumor Necrosis Factor (TNF) was first discovered in 1975 by English scientist Carswell and colleagues in the serum of mice infected with bacterial endotoxins or inoculated with the Bacillus Calmette-Guérin (BCG) vaccine. This substance was found to induce cytotoxic effects on various tumor cells in vitro, causing hemorrhagic necrosis in tumors without damaging normal cells, leading to its naming as Tumor Necrosis Factor [5]. The most common forms of TNF are TNF-α and TNF-β.

Tumor Necrosis Factors Overview

References

[1]Cao, X. T. Immunology in Medicine (6th ed.). Beijing: People's Medical Publishing House, 2015: 49. 

[2]Hou, Z. W., Huang, Y., et al. Research Progress on Engineered Cytokines[J]. Chinese Journal of Biological Products, 2023, 36(11): 1383-1390. 

[3]Jiang, B. C., Gao, Y. J. Chemokines and Their Receptors: Potential Therapeutic Targets for Neuropathic Pain[J]. Chinese Journal of Pain Medicine, 2020, 26(11): 805-813. 

[4]Lau, S., Feitzinger, A., Venkiteswaran, G., et al. A Negative-Feedback Loop Maintains Optimal Chemokine Concentrations for Directional Cell Migration[J]. Nature Cell Biology, 2020, 22(3): 266-273. 

[5]Gao, S. Y., Li, D. Tumor Necrosis Factor and Its Role in Cancer Research[J]. Chinese Pharmacological Bulletin, 2020, 36(9): 1209-1213.