I. Overview of Cytokines

Cytokines are small molecular proteins secreted by immune and non-immune cells. Through mechanisms such as autocrine and paracrine signaling, they bind to specific receptors on target cells to mediate immune regulation, cell growth and differentiation, inflammatory responses, and tissue repair. Characterized by high efficiency, multifunctionality, and overlapping functions, cytokines serve as key signaling molecules for maintaining immune homeostasis.

Figure 1. Overview of cytokine signaling[1]

Cytokines can be categorized into six classes based on their primary biological functions.

1. Interleukins

• Representatives: IL-1, IL-2, IL-4, IL-6, IL-10, IL-17, etc. (over 40 types currently identified).
• Characteristics: Initially considered factors produced by leukocytes to act on other leukocytes. The definition has since broadened to encompass a diverse group of cytokines with varying structures and functions, primarily responsible for intercellular communication. They exhibit extensive functions, participating in nearly all immune processes including activation, proliferation, chemotaxis, and differentiation.

2. Interferons

• Representatives:

Type I Interferons: IFN-α (primarily produced by plasmacytoid dendritic cells), IFN-β (primarily produced by fibroblasts). Primary function is antiviral.

Type II Interferon: IFN-γ (primarily produced by activated T cells and NK cells). Primary function is activating macrophages and enhancing cellular immune responses.

• Characteristics: Named for its ability to "interfere" with viral infection, its core functions are combating viral infection and regulating immunity.

3. Tumor Necrosis Factors

• Representatives: TNF-α (primarily produced by macrophages and T cells), Lymphotoxin (LT).
• Characteristics: Initially discovered for inducing tumor necrosis. Core functions include mediating inflammatory responses and apoptosis. Plays a critical role in autoimmune diseases and sepsis.

4. Colony-stimulating Factors

l Representatives: G-CSF, M-CSF, GM-CSF.

l Characteristics: Stimulates hematopoietic stem cells and progenitor cells to form cell colonies in semi-solid culture media in vitro. Core function: Regulates the differentiation and proliferation of hematopoietic cells (white blood cells, red blood cells, platelets, etc.).

5. Chemokines

• Representatives: IL-8 (CXCL8), MCP-1 (CCL2), RANTES (CCL5).
• Characteristics: A class of small-molecule cytokines with chemotactic activity. Their core function is to recruit leukocytes (such as neutrophils, monocytes, and lymphocytes) to sites of infection, injury, or inflammation. Based on the position of their cysteine residues, they are primarily divided into four subfamilies: CC, CXC, CX3C, and XC.

6. Growth Factors

• Representatives: Transforming Growth Factor-β (TGF-β), Epidermal Growth Factor (EGF), Vascular Endothelial Growth Factor (VEGF).
• Characteristics: A class of cytokines that stimulate cell growth, proliferation, and differentiation. Among these, TGF-β plays a particularly crucial role in the immune system, exhibiting potent immunosuppressive and anti-inflammatory effects closely associated with the function of regulatory T cells (Treg).

II. Interferons Overview

Interferons are a class of signaling proteins (cytokines) produced by immune cells and somatic cells in response to stimuli such as viral invasion and bacterial components. They are a key component of innate immunity and serve as a bridge connecting innate and adaptive immunity.

Interferons are primarily classified into Type I, Type II, and Type III based on their receptor specificity, amino acid sequence homology, and biological functions.

Type I Interferons—The Antiviral "Rapid Response Force"

This is the most numerous and crucial category, serving as the body's first line of specific defense against viruses.

• Key members:

IFN-α: Primarily produced by plasmacytoid dendritic cells, with multiple subtypes.

IFN-β: Primarily produced by fibroblasts.

Others: IFN-ω, IFN-κ, IFN-ε, etc. (with relatively specific or weaker functions).

• Primary Sources: Nearly all nucleated cells can produce type I interferons upon infection by viruses (or bacterial components, double-stranded RNA, etc.).
• Receptors: Share the same receptor complex—IFNAR (IFNAR1/IFNAR2).
• Core Functions:

Potent, rapid antiviral action: Establishes an "antiviral state" within cells by inducing expression of hundreds of "interferon-stimulated genes," inhibiting viral entry, replication, and assembly.

Immunomodulatory effects: Enhances expression of major histocompatibility complex (MHC) molecules, activates natural killer (NK) cells and dendritic cells (DCs), thereby bridging innate and adaptive immunity.

Figure 2. Activation of JAK/STAT and PI3K/AKT/mTOR pathways by type I interferons (IFNs)[2]

Type II Interferon—The "Master Regulator" of Immunity

This interferon family consists of a single member yet possesses potent functions, primarily responsible for immune regulation.

• Sole Member: IFN-γ.
• Primary Sources: Primarily produced by activated T lymphocytes (especially CD4⁺ Th1 cells and CD8⁺ cytotoxic T cells) and natural killer (NK) cells.
• Receptors: IFNGR (IFNGR1/IFNGR2).
• Core Functions:

Potent immune activation: A classic macrophage activator that significantly enhances phagocytosis and killing capacity.

Promotes Th1-type immune responses: Drives T cell differentiation toward the inflammatory Th1 subset.

Coordinates adaptive immunity: Enhances expression of MHC class I and II molecules, promoting antigen presentation.

 Figure 3. IFN-γ plays a central role in anti-tumor immunity[1]

Type III Interferons—The Mucosal "Special Guards"

This relatively late-recognized interferon family functions similarly to type I interferons but exhibits more restricted scope.

• Key Members: IFN-λ1, λ2, λ3 (also known as IL-29, IL-28A, IL-28B).
• Primary Sources: Primarily induced in specific cells such as epithelial cells and dendritic cells.
• Receptors: IL-10R2/IFNLR1. This receptor exhibits tissue-specific distribution, primarily expressed on epithelial cells and hepatocytes, while being absent or weakly expressed on most immune cells.
• Core Functions:

Mucosal Antiviral Defense: Functions overlap with type I interferons, inducing similar antiviral genes. However, due to limited receptor distribution, its effects are primarily confined to mucosal barrier surfaces (e.g., respiratory tract, intestines).

• Advantages: Provides effective local protection while avoiding systemic inflammatory responses, making it considered to have lower inflammatory side effects and a hotspot for new drug development.

Figure 4. Pathway of Type III IFN induction and signaling, and interaction of type III IFN with HSV[3]

III. Immune Defense Mechanism of Interferons

The immune defense mechanism of interferon is a multi-layered, multi-targeted precision process. Its core lies in inducing cells to produce an "antiviral state" while activating and coordinating the entire immune system, thereby establishing a robust defense network.

Phase 1: Direct Antiviral Effects (Establishing Defenses Within Infected Cells)

This represents interferon's most direct and rapid action. Upon detecting viral invasion, cells immediately produce and release interferon. The objective of this stage is: to confine the virus to the initial few infected cells before widespread dissemination occurs.

1. Alerting (Interferon Production): Viral nucleic acids (e.g., double-stranded RNA) produced during viral replication are potent interferon inducers. Cells recognize these components via pattern recognition receptors (e.g., RLRs, TLRs), triggering signaling pathways that initiate synthesis and secretion of type I interferons (IFN-α/β).

2. Spreading the alarm (paracrine and autocrine): Interferons secreted into the extracellular space act like alarm signals, affecting both the cell itself (autocrine) and surrounding uninfected neighboring cells (paracrine).

3. Establishment of an "antiviral state" (activation of the JAK-STAT pathway): Interferons bind to specific receptors on target cell surfaces, activating the classical JAK-STAT signaling pathway. This leads to the expression of hundreds of interferon-stimulated genes (ISGs), whose products serve as direct "weapons" executing antiviral functions.

Phase 2: Immunomodulation (Activation of Systemic Defense)

Interferons serve not only as "alarm systems" but also as the "command center" of the immune system, activating and regulating immune responses through multiple pathways.

1. Activation of innate immune cells:

Activates natural killer (NK) cells: Enhances their ability to recognize and kill virus-infected cells.

Activate macrophages: Enhance their phagocytosis and pathogen clearance capabilities.

2. Bridging and Initiating Adaptive Immunity:

Enhance antigen presentation: Interferons (especially IFN-γ) significantly upregulate the expression of MHC class I and II molecules on antigen-presenting cells (e.g., dendritic cells). This enables more efficient presentation of viral antigens to T cells, thereby strongly activating virus-specific CD8⁺ cytotoxic T cells (CTLs) and CD4⁺ helper T cells (Th cells), generating potent and persistent specific immunity.

 Figure 5. Interferon response triggered by viral infection[4]

This mechanism ensures the body can rapidly respond to viral threats and establish long-lasting protection. However, if this potent defense becomes uncontrolled—such as through excessive production or prolonged duration—it can also cause severe immunopathological damage, demonstrating its dual nature.

IV. Mechanism of interferon-mediated inflammatory storm

Interferons, particularly type I interferons (IFN-α/β) and type II interferons (IFN-γ), are core drivers of the cytokine storm. They do not act alone but, through a complex positive feedback loop, propel the immune system's "controlled burn" into an "uncontrolled explosion."

 Figure 6. Schematic representation of the mechanism of a cytokine storm[5]

The mechanism by which interferons mediate the cytokine storm represents a critical scientific question, revealing how immune responses transition from protective defense to pathological injury. This process is complex and involves cascade amplification effects, with the core mechanism summarized in the following key steps:

1. Initiation phase: Explosive production of interferons

• Trigger: In severe viral infections (e.g., influenza virus, SARS-CoV-2) or certain autoimmune diseases, massive pathogen replication or sustained immune activation triggers immune cells (e.g., plasmacytoid dendritic cells) and other nucleated cells to explosively produce large amounts of type I interferons.
• Turning Point: At this point, interferon concentrations and duration far exceed physiological levels, transforming from a localized defense signal into a systemic danger signal.

2. Amplification Phase: The Deadly "Positive Feedback Loop"

This is the critical mechanism behind the formation of the inflammatory storm. High concentrations of interferon drive an escalating inflammatory response through a potent positive feedback loop:

• Activation of Myeloid Cells: Type I interferons and IFN-γ powerfully activate macrophages and monocytes.
• Cytokine cascade: These overactivated myeloid cells then produce massive amounts of other pro-inflammatory cytokines, such as TNF-α, IL-6.
• Cyclic Amplification: Cytokines like TNF-α and IL-1 further stimulate type I interferon production and enhance IFN-γ effects. This creates a vicious cycle of "interferon → other pro-inflammatory factors → more interferon," exponentially amplifying inflammatory signals.

3. Injury Phase: Tissue Damage and Release of "Danger Signals"

• Direct and Indirect Damage: High levels of interferons and the resulting inflammatory mediators (e.g., TNF-α) exert direct toxicity on vascular endothelial cells and tissue cells. Simultaneously, the activated immune cells (e.g., CTLs, neutrophils) indiscriminately damage normal tissues while eliminating pathogens.
• Release of DAMPs: Upon cell death, tissue cells release internal substances like HMGB1 and ATP, known as damage-associated molecular patterns (DAMPs).
• Add Fuel to the Fire: DAMPs are recognized by pattern recognition receptors on innate immune cells (e.g., macrophages), triggering enhanced production of type I interferons and inflammatory mediators. This is akin to pouring a bucket of oil onto an already raging fire.

4. Final stage: Organ dysfunction

• Endothelial Barrier Disruption: Factors such as interferon and TNF-α disrupt the junctions between vascular endothelial cells, causing a sharp increase in vascular permeability. This leads to massive leakage of fluid and proteins into the interstitial spaces, resulting in tissue edema and hypovolemic shock.
• Microthrombosis: The inflammatory storm activates the coagulation system, forming diffuse thrombi within microvessels that obstruct organ blood supply.
• Multiple Organ Failure: The aforementioned processes collectively lead to acute respiratory distress syndrome (ARDS), acute kidney injury, heart failure, and other conditions that ultimately threaten life.

Summary and Clinical Implications

The mechanism of interferon-mediated inflammatory storms fundamentally involves the dysregulation of positive feedback regulation within the immune system. Acting as the "engine" of this network, interferon redirects its potent defensive capabilities toward self-attack.

Clinical Significance:

• Biomarkers: In severe infections like COVID-19, elevated levels of type I interferons and IFN-γ correlate strongly with disease severity and mortality risk.
• Therapeutic Targets: Targeting this pathway, the use of JAK inhibitors such as baricitinib and tocilizumab to suppress interferon signaling has become a key therapeutic strategy for treating critically ill patients and managing autoimmune diseases.

Understanding this mechanism helps us more accurately identify high-risk patients and intervene at the appropriate time, striking a balance between antiviral action and suppressing excessive inflammation.

V. Yeasen Interferon Series HiActi™ Cytokines

Recombinant proteins are widely used in core fields such as stem cell and organoid culture, recombinant protein therapeutics, CAR-T cell therapy, and antibody drugs. Amid the rapid expansion of the biopharmaceutical industry, the recombinant protein market is experiencing explosive growth, with demand for high-end raw materials rising annually. To precisely address the continuously evolving application needs in both research and industrial settings, Yeasen Biotech leverages years of R&D and production expertise to build an innovative recombinant protein expression and purification platform. This platform focuses on delivering high-activity recombinant protein products, targeting critical pain points such as low protein activity and inconsistent batch stability. Leveraging its proprietary expression and purification platform, Yeasen Biotech has developed the HiActi® cytokine series, including IFN-α, IFN-β, and IFN-γ. These products undergo rigorous quality control and cellular function validation to ensure high activity, purity, stability, and low endotoxin levels, helping you achieve optimal experimental results.

Product Data

Bioactivity of Human IFN-γ

Figure 7. The ED₅₀ as measured in antiviral assays using human HeLa cells infected with encephalomyocarditis (EMC) virus is 0.15–0.80 ng/mL.

Bioactivity of Mouse IFN-γ 

Figure 8. Measured in an antiviral assay using L-929 mouse fibroblast cells infected with encephalomyocarditis (EMC) virus. The EC₅₀ for this effect is 0.03-0.1 ng/mL.

Bioactivity of Mouse IFNA2 

Figure 9. Measured in an antiviral assay using L-929 mouse fibroblast cells infected with encephalomyocarditis (EMC) virus. The EC₅₀ for this effect is 20-200 pg/mL.

Ordering Information

Product Name	Cat. No.	Specification
Recombinant Human IFNA2 Protein	91223ES	10μg/50μg/100μg/500μg
Recombinant Mouse IFNA2 Protein	91219ES	10μg/50μg/100μg/1mg
Recombinant Human IFN-beta Protein	91221ES	2μg/10μg/50μg/100μg
Recombinant Mouse IFN-β, His Tag	91233ES	10μg/50μg/100μg
Recombinant Ovine IFN-τ	91217ES	10μg/100μg/500μg
Recombinant Human IFN-omega Protein	91227ES	20μg/100μg/250μg/500μg
Recombinant Human IFN-γ Protein	91207ES	20μg/50μg/100μg/500μg
Recombinant Mouse IFN-gamma Protein	91212ES	5μg/50μg/100μg/500μg
Recombinant Human IFN-λ1	91208ES	5μg/100μg/500μg
Recombinant Mouse IFN-λ2	91213ES	5μg/20μg/100μg/500μg
Recombinant Mouse IFN-λ3	91214ES	5μg/100μg/500μg

References:

1. Kureshi CT, Dougan SK. Cytokines in cancer. 2025; 43(1):15-35.

2. Schmeisser H, Bekisz J, Zoon KC. New Function of Type I IFN: Induction of Autophagy.  Journal of Interferon & Cytokine Research 2014; 34(2):71-78.

3. Yin Y, Favoreel HW. Herpesviruses and the Type III Interferon System..  . Virologica Sinica 2021; 36(4):577-587.

4. Smart A, Gilmer O, Caliskan N. Translation Inhibition Mediated by Interferon-Stimulated Genes during Viral Infections.  Viruses 2024; 16(7).

5. Karki R, Kanneganti T-D. The ‘cytokine storm’: molecular mechanisms and therapeutic prospects. 2021; 42(8):681-705.