Interleukins (ILs) are cytokines produced by several cell types that regulate immune cell activation, differentiation, proliferation, and migration.

Interleukins exert both pro-inflammatory and anti-inflammatory effects. Early research on cytokines began in the 1920s with studies on tissue factors in infection and allergy. In 1969, Dudley Dumonde coined the term “lymphokine” for immune mediators from lymphocytes, and by the early 1970s, specific factors like lymphocyte-activating factor (LAF) and osteoclast-activating factor (OAF) were identified. In 1974, Stanley Cohen introduced “cytokine” to describe signaling molecules produced by many cell types¹.

The term “interleukin” and the designation IL-1 originated at the second international lymphokine workshop in Switzerland in 1979². Since then, IL-1 has attracted widespread scientific interest across many fields due to its role as a biological mediator in nearly every organ system, leading to numerous important discoveries.

Cytokine genes evolved rapidly under host-parasite pressure, with many interleukins arising from gene duplications and co-evolving with their receptors, reflecting ancient origins in cell signaling³. Today, more than 60 cytokines have been identified and classified as interleukins since the discovery of IL-1 and IL-2 from monocytes and lymphocytes⁴.

Interleukins are proteins that regulate growth, differentiation, and activation in immune and inflammatory responses by binding to cell surface receptors and acting through paracrine and autocrine mechanisms. They perform a wide range of functions, including inducing fever, regulating immune responses, promoting or preventing inflammation, and influencing blood pressure and tissue repair. Their overproduction or deficiency can lead to autoimmune diseases, chronic inflammation, allergies, or infections. Several interleukins are potential targets for therapeutic treatments⁵.

Structural classification and nomenclature

Interleukins are a diverse group of proteins that vary in size and are structurally classified as class I or class II helical cytokines. Class I cytokines feature a four-helix bundle and are further subdivided into long-chain cytokines (over 165 amino acids, such as IL-6 and IL-11) and short-chain cytokines (under 165 amino acids, such as IL-2 and IL-4). In contrast, class II cytokines contain six or seven stacked helices and include IL-10-like and IL-28-like proteins, which share structural characteristics and gene organization with type I and type II interferons, forming the IL-10-IFN gene family³.

Major superfamilies and their function

IL-1 Superfamily: The IL-1 superfamily of cytokines regulates innate and adaptive immunity. It includes IL-1α/ β, IL-18, IL-33, IL-36, and IL-37, all sharing conserved β-trefoil folds and structurally similar receptors with Ig-like domains and intracellular toll/interleukin-1 receptor (TIR) domains⁶. The trefoil structure consists of three hairpins with two β-sheets each, displaying internal threefold symmetry stabilized by intramolecular hydrogen bonds⁷.

Signaling begins when a cytokine binds its primary receptor, then recruits an auxiliary receptor to form a hetero-trimeric complex that activates intracellular pathways.

Function: IL-1α acts as an alarmin damage-associated molecular pattern (DAMP) released during necrosis, where its active precursor triggers chemokine production that recruits neutrophils and then monocytes to the site of injury⁸.

Common γ-chain (γc) cytokines: The common cytokine receptor γ chain (γc) family shares a four α-helix-bundle structure and conserved motifs. These family of interleukins relies on γc for signaling.Since these cytokine receptors lack intrinsic kinase activity, they rely on associated JAK1 and JAK3 kinases to phosphorylate receptor subunits and activate STAT proteins. Once activated, STATs dimerize and translocate to the nucleus to regulate gene expression. Notable γ-chain cytokines include IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21^9,10.

Function: The γc family cytokines control the development, proliferation, survival, and differentiation of immune cells¹⁰.

IL-6/IL-12 Family

Cytokines of the IL-6/IL-12 superfamily belongs to class I cytokines or the β-trefoil structure. It guides naïve lymphocytes to differentiate into various T-helper, regulatory T cell, and regulatory B cell subsets essential for immune regulation. The IL-6 family includes IL-6, IL-11, CNTF, OSM, LIF, CT-1, and CLCF1, and these pleiotropic cytokines influence immunity, development, metabolism, and aging¹¹.

They signal by forming complexes with non-signaling α-receptors and gp130, activating JAK kinases and primarily recruiting STAT3 for downstream gene regulation.

Function: Gp130 cytokines regulate diverse biological processes such as hematopoiesis, immune responses, inflammation, cardiovascular function, and neuronal survival¹².

Mechanisms of signal transduction

The signaling pathway for cytokines primarily depends on the Janus kinase–signal transducer and activator of transcription (JAK–STAT) pathway, which transmits signals from cytokine receptors to the nucleus to regulate gene expression.

JAKs mediate signaling by associating with cytokine and growth factor receptors, which dimerize or oligomerize upon ligand binding to bring JAKs into close proximity. This proximity enables their activation through autophosphorylation or transphosphorylation, increasing their kinase activity¹³. Activated JAKs then phosphorylate receptor tyrosine residues, creating docking sites for SH2 domain–containing signaling proteins like STATs.

The unique STAT-binding motifs in each receptor determine which STATs are activated, and swapping these motifs can redirect signaling to activate different, even non-physiological, STATs¹⁴. For example, STAT5 proteins control vital cellular processes like proliferation, differentiation, and survival¹⁵. STAT3 drives tumor-promoting inflammation through NF-κB and IL-6–JAK pathways¹⁶, while STAT1 and STAT2 are central to regulating antiviral defense and adaptive immunity¹⁷.

Signal modulation

Signaling by plasma membrane receptors is tightly regulated through mechanisms such as endocytosis and ectodomain shedding. Endocytosis controls receptor internalization and directs them either toward degradation by proteolytic enzymes or recycling back to the membrane for another round of signaling. Endosomes also function as mobile signaling platforms that help propagate or modulate signals within the cell. In parallel, ectodomain shedding—a regulated proteolytic process—releases the extracellular domains of membrane-anchored proteins as soluble forms, such as cytokines, thereby extending the reach and efficiency of signal transduction pathways^18,19.

Interleukin-6 (IL-6) contributes to autoimmune diseases, chronic inflammation, and cancer through different modes of signaling²⁰. Classical IL-6 signaling occurs when IL-6 binds to the membrane-bound IL-6 receptor (mIL-6R) together with gp130 to transmit signals. IL-6 trans-signaling uses IL-6 bound to the soluble IL-6 receptor (sIL-6R), which then engages gp130 on target cells to activate downstream pathways.

Roles in innate immunity

Interleukins play essential roles in innate immunity by activating and recruiting immune cells, amplifying inflammatory responses, and coordinating the early defense against pathogens.

Early response to damage/invasion

The interleukin-1 (IL-1) family, plays a vital role in mediating inflammation. These IL are triggered by pattern-recognition receptors (PRR) called DAMPs. The members of the IL-1 family itself such as IL-1α and IL-33 can also act as DAMPs^7,8.

IL-1β and IL-18 are potent pro-inflammatory cytokines activated by bacteria, viruses, or danger signals. It is processed by inflammasome-forming NOD-like receptors (NLRs) through caspase-1 activation, driving innate immune responses linked to infection, inflammation, and autoimmunity²¹. IL-33 is released extracellularly in response to tissue damage, infection, or necrosis and acts as an alarmin to alert the immune system²².IL-36 secreted from epithelial cells amplifies the innate immunity response. For instance, active IL-36 stimulates keratinocytes to produce more IL-36, creating a forward feedback loop that intensifies neutrophil infiltration and skin inflammation²³.

Cellular recruitment and activation

Early cytokines trigger chemokine production and endothelial activation, recruiting neutrophils and monocytes to sites of infection or damage. Macrophages and dendritic cells produce IL-23, which sustains IL-17–producing T cells⁵. The mTOR pathway enables IL-23 to stimulate the action of neutrophils²⁴. Monocyte-derived IL-12 targets T cells to drive T-helper 1 (Th1) differentiation and strongly induces interferon-gamma production in T lymphocytes and NK cells⁵.IL-15 is essential for NK-cell homeostasis and enhances their cytotoxicity in diseases like cancer by modulating receptor frequency and expression²⁵.

Regulation

The secretion of interleukins is regulated by the action of other interleukins, such as⁵:

Th2-derived IL-10 suppresses Th1 responses by inhibiting IL-2 and IFN-γ, reducing antigen presentation, co-stimulation, and IL-12 production, while also downregulating pathogenic Th17 activity. IL-38, abundantly expressed in tissues like the placenta, tonsil B cells, spleen, skin, and thymus, inhibits T cell production of IL-17 and IL-22.

Roles in adaptive immunity

Interleukins regulate adaptive immunity by directing T and B cell development, differentiation, memory formation, and maintaining immune balance through inhibitory checkpoints to prevent autoimmunity.

T-cell development

IL-7 and other gamma-chain cytokines help maintain T cell viability and size, with IL-7 specifically supporting metabolic activity without inducing proliferation, highlighting that survival and trophic effects can be mechanistically separated²⁶.

Distinct cytokines are required to commit T cells to specific helper lineages, such as²⁷:

• IL-12 for Th1
• IL-4 for Th2
• IL-6 with TGF-β for Th17 cells
• IL-2/IL-10 for T-regulatory (T-reg) cells.

Dendritic cells produce many cytokines (eg, IL-1, IL-6, IL-10, IL-12, IL-23, IL-27, TNFα) in response to infections or inflammation, serving as essential signal cues for T cell differentiation. However, IL-4, which drives Th2 polarization, is notably not produced by dendritic cells.

B-cell maturation

IL-4 and IL-13 are vital cytokines in type-2 inflammation and are promising targets for treating allergic diseases. They drive IgE production, smooth muscle contraction, mucus secretion, and the recruitment of innate immune cells to inflamed tissues²⁸. IL-21 accelerates B cell cycle progression, enhancing their participation in germinal center responses across various B cell receptor affinities. This heightened proliferation also helps in explaining how IL-21 promotes plasma cell differentiation²⁹.

Cytokines like A proliferation-inducing ligand (APRIL), IL-6, and B cell activating factor (BAFF) are known to support the survival of both short-lived plasma cells (SLPCs) and long-lived plasma cells (LLPCs) across various organs. One of the key receptors for both BAFF and APRIL is B cell maturation antigen (BCMA), which is highly upregulated on plasma cells³⁰.

Memory formation

IL-7 and IL-15 cooperate to maintain memory CD8+ T cells, each partly compensating when the other is limited. Without IL-15, T cells become more reliant on IL-7 for survival and proliferation³¹. Tissue-resident memory T (TRM) cells are non-recirculating lymphocytes that rapidly clear pathogens at barrier sites. IL-9 is essential for their maintenance. For instance, IL-9 is used for mediating memory responses to airway allergens³².

Risks

The immune system must be tightly regulated to avoid damaging host tissues while fighting pathogens, relying on a balance of activating and inhibitory signals. Co-inhibitory receptors like PD1 and CTLA4 help prevent harmful immune activation by recognizing self-tissue ligands, ensuring potentially autoreactive T cells remain controlled. Dysregulation in these checkpoints can lead to autoimmunity. These checkpoints are usually targeted for therapeutic purposes in autoimmune diseases³³.

Interleukins beyond immunity

Interleukins extend beyond immunity by influencing processes such as tissue repair, metabolism, and microbiota regulations.

Metabolic and endocrine roles

Interleukin-6 (IL-6) promotes increased glucose production by the liver from multiple precursors and reduces insulin’s capacity to suppress glucose release and glycogen breakdown. Additionally, IL-6 contributes to systemic insulin resistance, supporting its role in driving hyperglycemia through combined metabolic and hormonal effects³⁴. IL-37/IL-38 are anti-inflammatory cytokines, acting like a metabolic brake that suppress innate and adaptive immune responses. IL-38 limits inflammatory macrophage activity by being released from apoptotic cells and interfering with inflammatory signaling. Dysregulation of IL-38 can lead to maladaptive immune responses³⁵.

Epithelial and microbiota regulation

IL-22 is essential for maintaining intestinal barrier integrity by supporting antipathogen defenses and epithelial regeneration. It is also used in junction tightening and has antimicrobial properties. For instance, a study shows reduced expression of the aryl hydrocarbon receptor (AhR), IL-22, and phosphorylated STAT3 correlates with lower antimicrobial production, potentially contributing to antibiotic-associated intestinal mucosal damage^36,37.

IL-26 is an antimicrobial protein produced by Th17 cells that can directly kill extracellular bacteria. For instance, in leprosy, researchers analyzed skin lesions and found IL-26 expression was higher in self-limited tuberculoid lesions than in progressive lepromatous lesions, suggesting a role in controlling intracellular pathogens like Mycobacterium leprae³⁸. In healthy skin, microbiota-responsive Tc17 cells produce IL-17 to regulate microbes, protect against fungi, and, upon injury, promote epithelial proliferation and wound healing through additional repair molecules³⁹.

Systemic effects

Interleukins can produce several system effects like regulation of body weight (weight gain or loss) depending on its release.

• IL-18 regulates body weight gain, energy intake, expenditure, and fat utilization⁴⁰.
• IL-1α andIL‑1β suppress appetite and drive cachexia by activating hypothalamic pathways and the HPA axis, leading to muscle wasting and increased energy use^41,42.
• Interleukin can act as an endocrine communicator and produce stress hormones. For example, IL-1 activates the hypothalamus-pituitary-adrenal axis under stress, triggering glucocorticoid release. These glucocorticoids influence memory and neural plasticity, with low levels being beneficial and high levels causing harm⁴³.

Interleukins in systems medicine

Interleukins serve as biomarkers and therapeutic targets to personalize treatments and predict disease outcomes across complex immune-related conditions.

Biomarkers

Interleukins serve as biomarkers for disease prognosis and progression in systemic conditions:

Sepsis: Levels of pro-inflammatory cytokines (IL-6, IL-8, IL-18, TNF-α) and the anti-inflammatory cytokine IL-10 rise can act as a biomarker in sepsis patients. Lower IL-6 is linked to better outcomes and excessive IL-10 has shown severe and fatal disease⁶⁴. Additionally, in sepsis, elevated soluble IL-2R-alpha (sIL-2Rα) levels correlate with greater disease severity and predict worse outcomes⁶⁵.

Psoriatic-artritis (PsA) progression: In PsA patients, levels of IL-6, IL-10, IL-17A, IL-17F, IL-22, TNFα, and IFNγ are high and linked to more active psoriasis inflammation. Additionally, IL-12/23p40, IL-23p19, IL-17A, and IL-17A/F inhibitors can be used to treat patients with extensive skin psoriasis^66,67.

Heart failure readmission:   Soluble ST2 receptor, along with its IL-33 ligand is an important prognostic marker in cardiovascular disease and a useful indicator for monitoring treatment in heart failure patients⁶⁸.

Precision medicine

Genomics and proteomics are enabling personalized predictions involving cytokines.

Polygenic risk scores (PRS) using exome and single nucleotide polymorphism (SNP) data from over 29,000 individuals in a biobank are being developed to predict inflammatory bowel disorder risk (including Crohn’s disease) and understand its genetic underpinnings for future prevention efforts⁶⁹.

Analysis of cytokine correlations in COVID-19 patients across different time points and disease severities showed that early levels of IFN-α2, IL-1β, IL-1Ra, and IL-6 could predict hospitalization with 76% accuracy and 79% sensitivity. However, this cytokine panel was less effective in predicting the need for invasive ventilation (33% sensitivity) or mortality (50% sensitivity)⁷⁰.

Dynamic cytokine panels are being explored to guide biologic dosing. For instance, a QSP model was developed to predict cytokine dynamics and cytokine release syndrome after CD3-bispecific dosing in solid tumors, illustrating how strategies like step-up dosing can manage toxicity and guide dose optimization across therapies⁷¹.

Off-target effects

IL-6 blockade improves LDL-cholesterol: In rheumatoid arthritis, IL-6 drives inflammation-related LDL cholesterol reduction through increased LDL catabolism, and IL-6 blockade normalizes lipid levels independently of clinical disease activity⁷².

Blocking IL-4Rα signaling unmasks effective immunity against adult filarial worms: For instance, a study shows that IL-4Rα–deficient mice control chronic filarial infection through residual eosinophilia driven by CCR3 and IL-5. Disruption of both pathways abolishes eosinophil recruitment and leads to susceptibility, revealing redundant Th2 mechanisms in protective immunity⁷³.

Safety and immune-related adverse events

Some of the immune related adverse consequences of interleukins include:

 Paradoxical flares

Sometimes, the use of certain blockers can cause paradoxical flares that can create unexpected inflammatory reactions. For instance: The use of anti-TNF biopharmaceuticals to treat inflammatory diseases such as psoriasis can lead to paradoxical psoriasis, where new or worse  ning psoriatic lesions develop even in patients without prior psoriasis. This reaction occurs in about 5% of patients and shows a slight predominance in women⁷⁴. Blocking IL4Rα or selectively IL13 can tilt immunity toward Th17/Th1 responses. This shift occasionally leads to new-onset eczema or psoriasiform lesions in atopic dermatitis patients⁷⁵.

Recombinant cytokine risks

Therapeutic cytokines frequently cause varied and sometimes severe side effects due to their broad biological actions, short half-lives, and ability to trigger cascades of other cytokines interacting with multiple receptors. The side effects can range from common mild reactions to serious hematologic, psychiatric, endocrine, neurologic, pulmonary, and dermatologic complications⁷⁶.

For instance, high dose IL-2 is an effective therapy in carcinoma and melanoma. However, it can cause capillary leak syndrome and cytokine-release effects. This can contribute to several complications⁷⁷.

Safety improvements

To mitigate these risks, several innovative methods are under development. For instance: IL‑2 is fused with PEG to extend half-life and direct activity toward effector (not regulatory) T cells⁷⁸.Intratumoral injection of IL‑2 achieves high local concentration, reducing systemic exposure⁷⁹. Nanoparticle delivery of recombinant IL-2 enables sustained tumor control in cancer immunotherapy while reducing systemic side effects⁸⁰. While IL-6 inhibitors have shown efficacy in several diseases, such as rheumatoid arthritis, their side effects have led to the development of JAK inhibitors as alternative treatments to block IL-6–mediated disease progression with potentially fewer adverse effects⁸¹.

Interleukins and the microbiota

Interleukins interact closely with the gut microbiota, aiding in immune regulation and influencing inflammation.

Homeostasis

T cells are important in maintaining homeostasis in the intestine. For instance, gut microbiota–derived short-chain fatty acids promote IL-10 production by antigen-specific Th1 cells via G-protein coupled receptor 43 (GPR43) signaling. This works through the activation of STAT3 and mTOR pathways to maintain intestinal homeostasis⁸².

Segmented filamentous bacteria (SFB) stimulate both IL-17 and IL-22 production in the small intestine. ILC3 cells serve as the main source of IL-22 through IL-23–dependent signaling. Disruption of the IL-23R/IL-22 pathway can result in uncontrolled SFB expansion, highlighting the delicate balance between protective immunity and potential autoimmunity⁸³.

Dysbiosis effects

Dysbiosis can cause leaky-gut and develop infections. For instance, butyrate, produced by gut microbiota, regulates immunity by activating regulatory T cells and suppressing pro-inflammatory cytokines. It not only inhibits IL-12, TNF-α, IL-1β, and nitric oxide while boosting IL-10 to control intestinal inflammation. When butyrate-producing bacteria are depleted through dysbiosis, barrier dysfunction and infection risk increase as it reduces IL-10 production⁸⁴.

Therapeutic restoration

Therapeutic restoration, like fecal microbiota transplantation (FMT), improves active ulcerative colitis by reducing pro-inflammatory cytokine levels such as IL-1β and IL-6 in both the gut lining and the bloodstream⁸⁵.

Viruses and interleukin hijacking

Viruses can hijack interleukin pathways by producing cytokine mimics or manipulating host signaling such as:

Epstein-Barr virus (EBV) produces viral interleukin-10, an ~80% homolog of human IL-10 encoded by the BCRF-1 gene, which helps the virus evade host antiviral immunity and establish latency⁸⁶. Cytomegalovirus UL144 binds to the Ig superfamily member B T lymphocyte attenuator(BTLA), imitating herpesvirus entry mediator (HVEM)–BTLA interactions and suppresses T-cell proliferation in vitro⁸⁷. NLRP3 inflammasome activation in COVID-19 drives excessive production of IL-1β and IL-18, fueling a cytokine storm that activates platelets, endothelial cells, and neutrophils, worsening respiratory symptoms⁸⁸.

Crosstalk with non-cytokine networks

Cytokines, inflammatory mediators, neuropeptides, and neurotransmitters drive crosstalk and positive-feedback loops linking diverse immune cells with all branches of the nervous system. Synergistic interactions occur when multiple mediators or signals combine to amplify immune responses beyond the effect of each factor alone. For example: IL-17A and TNF work together to strongly induce proinflammatory mediators in synovial fibroblasts, contributing to chronic arthritis. This synergistic effect is mediated through IκBζ-dependent induction of the transcription factor ELF3, which regulates the inflammatory factors⁸⁹.

The neuropeptide substance P and IL-33 act together to strongly activate mast cells, leading them to release the proinflammatory cytokines IL-1β and TNF-α. This synergistic response is linked to the development and progression of psoriasis⁹⁰.

Dysregulation and human disease

Dysregulation of cytokine signaling is a key driver of various human diseases, including autoimmune disorders, chronic inflammation, and cancer.

Genetic associations

In genomics, polymorphism refers to the existence of two or more variants of a specific DNA sequence within a population⁹¹. Some of the interleukins that are affected by polymorphism include: IL-17 family polymorphisms affect psoriasis severity, treatment response, and disease susceptibility. Additionally, specific polymorphisms of TNF-α and IL-23 play a significant role in determining disease severity and responsiveness to anti-TNF therapies⁹².Polymorphisms in IL2RA, which encodes the IL-2 receptor alpha subunit (CD25), are associated with increased risk of developing type 1 diabetes⁹³.Polymorphisms in the IL‑10 promoter region are linked to an increased risk of developing Crohn’s disease⁹⁴.

Interleukin-33 and its receptor ST2 are asthma susceptibility genes that act as alarmins released by airway epithelial cells upon damage or allergen exposure. Various polymorphisms contribute to childhood asthma development. Interleukin-6 polymorphisms are linked to increased cardiovascular risk factors in patients with premature coronary artery disease⁹⁵.IL-18 promoter polymorphisms at position -607 may increase IL-18 production, thereby contributing to increased disease activity and faster progression of SLE in patients⁹⁶.

Loss-of-function mutations

Loss-of-function mutations reduce or eliminate the activity of a cytokine gene product causing deficiencies. Silent mutation of IL-7Rα receptor causes severe combined immunodeficiency (SCID) by disrupting splicing⁹⁷. Interleukin-17 receptor A deficiency is an inherited disorder causing chronic mucocutaneous candidiasis⁹⁸. Inherited IL-10 or IL-10 receptor deficiencies cause very early-onset inflammatory bowel disease (IBD), colitis, and perianal fistulas⁹⁹.

Over-activity disorders

Over-activity disorders are conditions where excessive cytokine production, causing several diseases. Cryopyrin-associated periodic (CAP) syndromes are autoinflammatory diseases caused by NLRP3 gain-of-function mutations that trigger excessive IL-1β secretion¹⁰⁰. IL-6 trans signalling, where IL-6 activates cells via the soluble IL-6 receptor, contributes to the development of various diseases including Castleman disease, cancers, autoimmune disorders, and cardiovascular conditions¹⁰¹.

Oncology

Disturbances in cytokine signaling can disrupt the tumor microenvironment, leading to chronic inflammation and metastasis. For example: Local and systemic IL-6 overexpression is found in several cancers, including breast cancer. For instance, elevated IL-6 levels in the blood are linked to poor prognosis and lower survival rates in breast cancer patients¹⁰². Tumors evade the immune system by releasing immunosuppressive cytokines like IL-10 and TGF-β into their microenvironment. IL-17 promotes tumor growth by creating tumor-supportive microenvironments and increasing myeloid-derived suppressor cells (MDSC)^103,104.

Metabolic diseases

Cytokines like TNF-α, IL-6, and IL-1β drive metabolic disorders by promoting insulin resistance and inflammation, highlighting opportunities for treatments such as anticytokine therapies and lifestyle changes¹⁰⁵. High levels of cytokines like IL-6, and IL-1β also drive the low-grade inflammation seen in obesity¹⁰⁶. Liver inflammation, driven in part by IL-6, is essential in progressing simple steatosis (fatty liver) to steatohepatitis (fatty liver with inflammation) in metabolic disease¹⁰⁷.

Anti-inflammatory cytokines

Therapeutic targeting

Multiple strategies are employed for therapeutic targeting, such as:

Blocking pathogenic signals: Monoclonal antibodies such as tocilizumab, sarilumab, and siltuximab block the IL-6 binding to its receptor and are widely used to treat immune-mediated inflammatory rheumatic diseases (IMIRDs)¹⁰⁸. Apart from this, high-dose anakinra, an interleukin-1 blocker, has been used to treat COVID-19 patients with acute respiratory distress syndrome and hyperinflammation¹⁰⁹.

Augmenting deficient pathways: Improvingdeficient pathways involves enhancing weakened or insufficient immune signals. For instance, a study found that combining a melanoma vaccine with high-dose interleukin-2 improved response rates in metastatic melanoma patients compared to interleukin-2 alone, supporting this strategy to enhance antitumor immunity¹¹⁰. IL-15 can also stimulate the body’s immunosuppressive mechanisms¹¹¹.

Using cytokines as adjuvants/cell-therapy boosters: Cytokines used as vaccine adjuvants enhance antitumor immunity by boosting effector cell proliferation, cytotoxicity, and cytokine production. For instance, For instance, the FDA approved IL-2 as a single-agent treatment for metastatic renal-cell carcinoma and melanoma. IL-2 has also shown efficacy as a vaccine adjuvant against infections¹¹¹.

Monoclonal antibodies

Numerous monoclonal antibodies target interleukins or their receptors. Examples include:

Canakinumab (anti–IL-1β): It targets IL-1β and is being tested in atherosclerosis¹¹². It has also shown promising safety, favorable pharmacokinetics, and potential effectiveness for treating a rare inherited inflammatory disorder called cryopyrin-associated periodic syndromes (CAPS)¹¹³.

Ustekinumab (anti–IL-12/23p40): Ustekinumab was the first biologic approved for Crohn’s disease that targets the IL-12/23p40 pathway. Phase III trials showed it was superior to placebo in inducing and maintaining clinical remission¹¹⁴.

Guselkumab (anti–IL-23p19): Guselkumab, which inhibits the IL-23p19 subunit, delivers sustained improvement in the signs and symptoms of active psoriatic arthritis¹¹⁵.

Bimekizumab (dual IL-17A and IL-17F inhibitor): Bimekizumab is the first human monoclonal antibody to specifically inhibit both IL-17A and IL-17F and has been evaluated in multiple phase II/III trials for psoriasis and psoriatic arthritis¹¹⁶.

Dupilumab (anti–IL-4Rα): Dupilumab blocks IL-4 and IL-13, used to treat eczema and asthma¹¹⁷.

Advanced therapies

As systemic cytokine therapy is limited by toxicity and poor tumor targeting, localized delivery directly into tumors may enhance efficacy and safety. Some of the advanced strategies include:

Intratumoral injection of lipid nanoparticles (LNPs) carrying IL-12 and IL-27 mRNAs synergistically suppresses tumor growth without systemic toxicity. This approach also triggers strong infiltration of IFN-γ and TNF-α producing NK cells and CD8+ T cells, highlighting a promising new strategy for cancer treatment¹¹⁸. Blocking the interleukin-6 receptor with a combination of tocilizumab, ipilimumab and nivolumab can help reduce immune-related toxicity from ipilimumab-nivolumab treatment alone in metastatic melanoma¹¹⁹.

CRISPR-based epigenome editing uses dCas9 fused to activators or repressors to precisely regulate cytokine receptor genes, improving cell therapies for musculoskeletal diseases. By targeting inflammatory cytokines like TNF-α and IL-1β, this approach helps prevent tissue degradation and cell death driven by NF-κB signaling¹²⁰.

Personalized medicine and companion diagnostics

Personalized medicine uses interleukin profiling to tailor therapies, enhancing treatment precision and safety.

Predictive biomarkers

IL-17A/IL-23p19 acts as a predictive marker for guselkumab response. For instance, inhibiting IL-23 p19 with guselkumab in PsA patients significantly reduced Th17 effector cytokines to levels comparable to those of healthy controls¹²¹. Soluble ST2 receptor serves as a biomarker for left ventricular dysfunction and functional status in patients with inflammatory cardiomyopathy¹²².

Molecular imaging

Radiolabeled interleukin-1 receptor antagonist enables imaging of synovitis in rheumatoid arthritis patients¹²³. For instance, radiolabelled-Anakinra, a modified IL-1 receptor antagonist, improves symptoms and slows disease progression in rheumatoid arthritis with a favorable safety profile and fewer serious infections than TNF blockers. It can be visualized using molecular imaging, such as magnetic resonance imaging (MRI) or positron emission tomography (PET)¹²⁴.

Lifestyle and genetics

The IL-6 rs1800795 gene polymorphism is linked to sedentary behavior and less physical exercise that causes an increased risk of cardiovascular diseases, obesity, and diabetes. The rs1800795 code is a single-nucleotide polymorphism located in the promoter region of the IL-6 gene^125,126.

Environmental and evolutionary perspectives

Chromosomal and sequence analyses reveal that nine IL-1 receptor family members likely arose from duplication and modification of a proto-IL-1R1 receptor¹²⁷.

• IL-1 ligands evolved from proto-IL-1β through gene duplications.
• IL-18 and IL-33 lack sequence and chromosomal similarity, suggesting separate origins.
• IL-1α arose from IL-1β duplication and diverged due to distinct functional pressures.

Species variation

Cytokine profiles vary in different species to adapt to their unique biological and environmental challenges. Extensive genomic analysis has shown that fish lack orthologues of several mammalian IL-1 family cytokines¹²⁸. Dampened NLRP3 inflammasome activation in bats limits their cells' ability to produce the pro-inflammatory cytokine IL-1β¹²⁹.

Evolutionary selection

Evolutionary selection has shaped the diversity and function of interleukins to meet the distinct immune challenges faced by different species over time. Since its discovery in 1989, IL-10 has been recognized for its conserved anti-inflammatory and regulatory roles across vertebrates, with viral IL-10s showing similar effects¹³⁰. Recent studies show that IL-10 promoter variants are now linked to chronic diseases, such as acute coronary syndromes, regulating the gene expression levels¹³¹.

Environmental influences

Environmental factors can modulate the expression and activity of interleukins, thereby impacting immune responses and inflammation such as: Aeroallergen increases the production of thymic stromal lymphopoietin (TSLP) and IL-33, which mutually boost each other’s lung protein and ILC2 receptor expression, intensifying innate type-2 airway inflammation¹³². Urban particulate matter increases IL-6 while reducing IL-8 secretion in airway epithelial cells. This can cause several diseases, such as asthma¹³³.

Future directions

Context-specific modulation: A dynamic model of common γ-chain cytokines reveals that receptor trafficking is critical for accurately predicting ligand responses across diverse biological contexts. By integrating tensor factorization and pathway modeling, researchers can map cytokine responses across cell types and design ligands with improved selectivity. Tensor factorization helps visualize how input-output behaviors of cytokine families vary across time, cell types, ligands, and concentrations¹³⁴.

Designer cytokines: “Designer cytokines” are engineered versions of TNF and interferon-γ tailored to target CD13-positive (myeloid-derived) tumor vasculature. These cytokines enhance local immune activity while minimizing off-target effects by reducing receptor binding affinity on normal cells¹³⁵.

Regenerative medicine: IL-22 promotes epithelial cell regeneration and tissue protection. In optimized human intestinal organoid models, IL-22 has been shown to drive the formation of Paneth cells—specialized secretory cells in the small intestine—and stimulate the expression of antimicrobial defense genes across multiple intestinal cell types¹³⁶ ¹³⁷.

Ethical considerations: As cytokine modulation and gene-editing techniques like CRISPR advance, ethical concerns arise. These include safety, informed consent, and broader issues of justice and equity—especially given the ecosystem-wide and long-term implications of editing immune signaling pathways.

FAQs

What is the difference between pro-inflammatory and anti-inflammatory interleukins?

Pro-inflammatory interleukins, such as IL-1 and IL-6, stimulate the activation of immune cells and inflammation to combat infections or repair tissue damage. In contrast, anti-inflammatory interleukins, such as IL-10 and IL-37, suppress excessive immune responses to prevent tissue injury and maintain balance.

What roles do interleukins play in cancer development and therapy?

Interleukins, such as IL-33 can promote cancer by supporting tumor growth, inflammation, and immune evasion. Conversely, some interleukins, such as IL-2 are used therapeutically to boost anti-tumor immunity in cancer treatment.

How do interleukins influence vaccine efficacy and immune memory?

Interleukins, such as IL-15 enhance vaccine efficacy by promoting the activation and expansion of T and B cells. They also support the formation of long-lived memory cells that provide lasting protection against pathogens.

Meta title: Interleukins: Roles in immunity and beyond | Abcam

Meta description: Explore interleukins, the key drivers of the immune system. Learn about their functions and emerging therapies for autoimmune diseases, infections, and cancers.

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