Introduction

Interleukins (ILs) are a large family of cytokines that function as key mediators of immune cell communication, regulating cell proliferation, differentiation, motility, and survival across both innate and adaptive immunity.[1] The term interleukin was first introduced in the late 1970s to describe leukocyte-derived cytokines, with IL-1 identified as a leukocytic pyrogen and IL-2 as a T-cell growth factor. Since then, more than 60 cytokines have been designated as interleukins, and to date, at least 38 have been formally recognized (IL-1 through IL-38).[2]

Interleukins are structurally diverse but are commonly grouped into families based on receptor usage, sequence homology, and biological function. Major families include the following:

• IL-1 family: IL-1α, IL-1β, IL-18, IL-33, IL-36, IL-37, and IL-38
• Common γ-chain family: IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21
• IL-6/IL-12 family: IL-6, IL-11, IL-12, IL-23, and IL-27
• IL-17 family: IL-17A through IL-17F and IL-25

Each family orchestrates specific pathways in host defense, inflammation, hematopoiesis, and tissue repair.[1][2][3][4]

From a historical perspective, IL-1 and its receptor antagonist (IL-1Ra) have become the prototypes for understanding the balance between pro- and anti-inflammatory cytokines.[5] IL-2, initially described as a T-cell mitogen, was later shown to play a central role in immune regulation and tolerance.[6] IL-10 emerged as a master anti-inflammatory cytokine, functioning as a key regulator in infection and autoimmunity.[7][8][9] The discovery of T-helper (Th)17 cytokines, particularly IL-17 and IL-23, provided new insights into chronic inflammation and autoimmunity.[10][3] Collectively, these discoveries established the conceptual framework that interleukins act not only as immune stimulators but also as immunoregulators.

Clinically, interleukins have become both biomarkers and therapeutic targets. Dysregulated signaling is implicated in autoimmune diseases, such as rheumatoid arthritis, inflammatory bowel disease, and psoriasis, as well as in malignancies, infections, and hyperinflammatory states, including cytokine storms. Therapeutic blockade of interleukin pathways, including anakinra (IL-1Ra), tocilizumab (IL-6 receptor blocker), and secukinumab (IL-17A inhibitor), has transformed management across rheumatology, dermatology, oncology, and infectious diseases.[2][11]

Function

Interleukins exert pleiotropic and often overlapping roles in regulating immune and inflammatory responses. The principal functions of interleukins include the activation, proliferation, and differentiation of leukocytes, the orchestration of innate and adaptive immunity, and the regulation of hematopoiesis and tissue repair.[2] A hallmark of interleukin biology is pleiotropy, where an interleukin can have multiple effects on different cell types, and redundancy, in which several interleukins mediate similar biological functions.[1][12]

Functionally, interleukins can be categorized into several broad groups:

• Pro-inflammatory mediators: Interleukins such as IL-1, IL-6, IL-17, and IL-18 are cytokines that promote fever, acute-phase responses, neutrophil recruitment, and autoimmunity.[13][3]
• Immunoregulatory and anti-inflammatory cytokines: Interleukins, including IL-10, IL-37, and IL-38, counteract excessive inflammation and promote tolerance.[7]
• Growth and differentiation factors: Important interleukins include IL-2 (T-cell proliferation and regulatory T-cell survival), IL-4 and IL-5 (allergic immunity and eosinophil activation), and IL-7 and IL-15 (lymphocyte survival and natural killer cell development).[14][15]
• Tissue repair and barrier immunity regulators: Interleukins, such as IL-22, IL-25, and IL-33, play an important role in maintaining epithelial integrity, mucosal defense, and wound healing.[2][16][11]

Several interleukins are considered signature cytokines due to their distinct biological functions. IL-1 family members (IL-1α and IL-1β) are central pro-inflammatory mediators that drive fever and inflammasome activation.[13][5] IL-2, initially characterized as a T-cell growth factor, is now recognized as essential for both T-effector proliferation and the survival of regulatory T cells, highlighting its dual role in immune activation and tolerance.[6] IL-6 promotes B-cell maturation, acute-phase protein production, and systemic inflammation, and is a key driver of cytokine storm syndromes.[11] IL-10 functions as the master regulator of anti-inflammatory responses, suppressing Th1 and Th17 activity while maintaining immune homeostasis.[7][8][9] The IL-17/IL-23 axis promotes neutrophil recruitment and has become a therapeutic target in psoriasis and inflammatory bowel disease.[10][3] Finally, IL-22 serves as a key mediator of mucosal barrier protection and epithelial regeneration.[2][16]

To aid in quick reference, the major interleukins, their cellular sources, principal functions, and clinical associations are summarized in Table 1.

Table

Table 1. Overview of Interleukin Families and Their Clinical Implications.

Abbreviations: IL, interleukin; DCs, dendritic cells; NK, natural killer; Treg, regulatory T cells; Th, T helper cells; ILC, innate lymphoid cells; Tfh, T follicular helper cells; SCID, severe combined immunodeficiency; IFN-γ, interferon-gamma; RA, rheumatoid arthritis; IBD, inflammatory bowel disease; RCC, renal cell carcinoma; SLE, systemic lupus erythematosus; COPD, chronic obstructive pulmonary disease; gp130, glycoprotein 130; CXCR, C-X-C chemokine receptor; IgE, immunoglobulin E.

Issues of Concern

Despite major advances in cytokine biology and therapeutics, several challenges remain. The pleiotropic and redundant nature of interleukins complicates the interpretation of biomarkers and the design of targeted therapies, as blocking one pathway may activate compensatory mechanisms.[2][12] Biologic therapies targeting the IL-6 or IL-17 pathways are associated with an increased risk of opportunistic infections, such as tuberculosis and herpes zoster, requiring careful screening and monitoring.[13][11] High costs also limit accessibility, particularly in resource-constrained settings, and a subset of patients demonstrate primary or secondary non-response to biologic agents.[10][3] Furthermore, variability in early clinical trial outcomes, such as those observed with IL-6 blockade in COVID-19, has been resolved through post-2021 data, which emphasize context-specific efficacy. Tocilizumab is approved for use in hospitalized patients who receive systemic corticosteroids and require supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation.[17]

Clinical Significance

Interleukin signaling has critical implications in human disease, and the dysregulation of specific interleukins contributes to a diverse range of pathologies, including autoimmune conditions, allergies, malignancy, and infection.[2] Consequently, interleukins have become both diagnostic biomarkers and therapeutic targets in clinical practice.

Autoimmune and Inflammatory Diseases

• IL-1 plays a central role in autoinflammatory syndromes, such as systemic juvenile idiopathic arthritis and cryopyrin-associated periodic syndromes. Blockade with anakinra (an IL-1 receptor antagonist) or canakinumab (an anti–IL–1β antibody) provides significant clinical benefit.[13]
• IL-6 is strongly implicated in rheumatoid arthritis, Castleman disease, and cytokine release syndromes. IL-6 receptor inhibition with tocilizumab or sarilumab reduces inflammation and has been approved for both rheumatologic disorders and severe COVID-19.[13][11]
• IL-17 and IL-23 drive chronic inflammatory diseases, including psoriasis, ankylosing spondylitis, and inflammatory bowel disease. Monoclonal antibodies, including secukinumab and ixekizumab (anti–IL-17A) and ustekinumab and guselkumab (anti–IL-12/23), have revolutionized treatment in dermatology and gastroenterology.[10][3]

Oncology and Immunotherapy

• IL-2 was one of the first interleukins used in cancer immunotherapy, particularly in metastatic melanoma and renal cell carcinoma. Although high-dose IL-2 therapy induces durable responses in a minority of patients, its severe toxicity limits widespread use.[3][6] Current research focuses on engineered IL-2 variants to optimize efficacy while minimizing adverse effects.
• Other cytokines, such as IL-15 and IL-21, are being investigated as adjuvants to enhance cytotoxic T-cell and natural killer cell responses in cancer immunotherapy.[2][15]

Infectious Disease and Cytokine Storm

• Elevated IL-6 levels are strongly correlated with sepsis severity and have been widely used as biomarkers during the COVID-19 pandemic, where IL-6 blockade has demonstrated improved outcomes in selected patients.[11][17]
• IL-10 production can be protective during infection by limiting tissue damage, but its overexpression may promote pathogen persistence and is associated with poor outcomes in viral infections.[7][8]

Allergic and Atopic Disease

• IL-4 and IL-13 drive immunoglobulin E (IgE) class switching and mucus production, playing central roles in asthma and atopic dermatitis. Targeted biologics such as dupilumab (anti–IL-4Rα) significantly improve symptoms in moderate-to-severe cases.[2][14]
• IL-5 mediates eosinophil differentiation and activation; antagonists including mepolizumab and reslizumab are effective in eosinophilic asthma.[2][13]

Taken together, advances in cytokine biology have enabled the development of precision biologic therapies, many of which are now standard of care across immunology, rheumatology, dermatology, and oncology.[2] A more detailed overview of major interleukins, their cellular sources, biological functions, and clinical associations is summarized in Table 1. A concise review of interleukin-modifier drugs is given below. For comprehensive prescribing information, please refer to the Food and Drug Administration (FDA)-approved product labels.

Food and Drug Administration–Approved Drugs with Indications

Therapeutic interleukins: Recombinant interleukins are used to directly modulate the immune system.

• Aldesleukin: A recombinant human IL-2, approved for the treatment of metastatic renal cell carcinoma and metastatic melanoma.[18] Refer to the FDA-issued box warning below.
• Oprelvekin: A recombinant human IL-11, approved for the prevention of severe chemotherapy-induced thrombocytopenia in adult patients with non-myeloid malignancies.[19] The clinical use is limited due to the associated adverse effects and withdrawal from the market.[20]

Interleukin modifiers: Interleukin modifiers are monoclonal antibodies or receptor antagonists that specifically block the action of certain interleukins. Clinical indications are given below.

• IL-1 pathway: These drugs block the proinflammatory effects of IL-1 in various autoinflammatory diseases.

  • Anakinra: An IL-1 receptor antagonist, approved for rheumatoid arthritis, deficiency of interleukin-1 receptor antagonist, cryopyrin-associated periodic syndromes.[21][22][23][22]
  • Canakinumab: A human monoclonal antibody targeting IL-1β. This drug is indicated for cryopyrin-associated periodic syndromes, Still disease, familial Mediterranean fever, and other autoinflammatory conditions, including gout flares.[24][25][26][25]
  • Rilonacept: A soluble IL-1 decoy receptor, approved for cryopyrin-associated periodic syndromes and familial Mediterranean fever.[27][28]

• IL-4 and IL-13 pathway: These drugs block the pathway involved in allergic and type 2 inflammation.

  • Dupilumab: A human monoclonal antibody that blocks the IL-4 receptor alpha subunit, inhibiting both IL-4 and IL-13 signaling. Dupilumab is indicated for moderate-to-severe atopic dermatitis when topical therapy is inadequate or inadvisable, with or without topical corticosteroids.[29] Dupilumab is also approved for other dermatologic diseases, including prurigo nodularis, chronic spontaneous urticaria refractory to H1 antihistamines, and bullous pemphigoid.[30][31][32] This medication is also indicated as add-on maintenance therapy for asthma with an eosinophilic phenotype, chronic rhinosinusitis with nasal polyps, and COPD with an eosinophilic phenotype. In addition, dupilumab is approved for eosinophilic esophagitis.[33][34][35][36]
  • Tralokinumab: A human monoclonal antibody that specifically targets and neutralizes IL-13. This medication is approved for atopic dermatitis.[37]

• IL-5 pathway: These drugs specifically target IL-5, a key cytokine in eosinophil-driven diseases.

  • Mepolizumab: A humanized monoclonal antibody that targets IL-5. This medication is approved for severe eosinophilic asthma, eosinophilic granulomatosis with polyangiitis, and hypereosinophilic syndrome.[38][39] Mepolizumab has recently gained approval for add-on maintenance therapy in adult patients with inadequately controlled COPD characterized by an eosinophilic phenotype.[40] Mepolizumab is not recommended for asthma or COPD exacerbations.
  • Reslizumab: A humanized monoclonal antibody that targets IL-5. This medication is approved for add-on maintenance treatment of severe eosinophilic asthma in adults.[41]
  • Benralizumab: A humanized monoclonal antibody that targets the IL-5 receptor alpha, leading to direct depletion of eosinophils. This medication is approved for severe eosinophilic asthma and eosinophilic granulomatosis with polyangiitis.[42][43]

• IL-6 pathway: These agents block the inflammatory effects of IL-6.

  • Tocilizumab: A humanized monoclonal antibody that targets the IL-6 receptor. This medication is approved for rheumatoid arthritis, giant cell arteritis, polyarticular and systemic juvenile idiopathic arthritis, and systemic sclerosis-associated interstitial lung disease. Tocilizumab has been used to treat cytokine release syndrome. Tocilizumab is also approved for COVID-19 in hospitalized adult patients who are receiving systemic corticosteroids and require additional respiratory support.[44]
  • Sarilumab: A human monoclonal antibody that targets the IL-6 receptor, approved for moderate-to-severe active rheumatoid arthritis in adults.[45] In addition, it is now FDA-approved for polymyalgia rheumatica in patients with an insufficient response to corticosteroids and active polyarticular juvenile idiopathic arthritis.[46]
  • Siltuximab: Siltuximab, a chimeric monoclonal antibody, binds IL-6 and precludes the binding of IL-6 to soluble and membrane-bound IL-6 receptors. This medication is approved for multicentric Castleman disease in patients who are HIV-negative and human herpesvirus-8-negative.[47][48]

• IL-12 and IL-23 pathway: These drugs target cytokines involved in the differentiation of Th1 and Th17 cells, which play a crucial role in various autoimmune diseases.

  • Ustekinumab: A human monoclonal antibody that targets the p40 subunit shared by both IL-12 and IL-23. This medication is approved for plaque psoriasis, psoriatic arthritis, Crohn disease, and ulcerative colitis.[49][50][51]

• IL-17 pathway: These drugs inhibit the IL-17 pathway, a key driver of inflammation in specific conditions.

  • Secukinumab: A human monoclonal antibody that targets IL-17A. This medication is approved for plaque psoriasis, psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, hidradenitis suppurativa, and juvenile idiopathic arthritis.[52][53]
  • Ixekizumab: A humanized monoclonal antibody that targets IL-17A. This medication is approved for plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis.[54]
  • Brodalumab: A human monoclonal antibody that targets the IL-17 receptor. This medication is approved for moderate-to-severe plaque psoriasis in adults.[55] Brodalumab carries an FDA-issued box warning for suicidal tendency.[56]
  • Bimekizumab: A humanized monoclonal antibody that targets both IL-17a and IL-17f. This medication is approved for moderate-to-severe plaque psoriasis in adults and active psoriatic arthritis.[57] Bimekizumab has also been approved for use in adult patients with active non-radiographic axial spondyloarthritis, active ankylosing spondylitis, and moderate-to-severe hidradenitis suppurativa.[58][59]

• IL-23 pathway: These drugs are more specific IL-23 inhibitors that target the p19 subunit.

  • Guselkumab: A human monoclonal antibody that targets the p19 subunit of IL-23. This medication is approved for moderate-to-severe plaque psoriasis and active psoriatic arthritis.[60] Recently, it has also been approved for moderate-to-severe active ulcerative colitis and Crohn disease.[61][62]
  • Risankizumab: A humanized monoclonal antibody that targets the p19 subunit of IL-23. This medication is approved for moderate-to-severe plaque psoriasis, active psoriatic arthritis, and moderately to severely active Crohn disease and ulcerative colitis.[63][64][63]
  • Tildrakizumab: A humanized monoclonal antibody that targets the p19 subunit of IL-23. This medication is approved for moderate-to-severe plaque psoriasis.[65]
  • Mirikizumab: A humanized monoclonal antibody that targets the p19 subunit of IL-23. This medication is approved for moderate-to-severe active ulcerative colitis in adults.[66][67]

• IL-31 pathway

  • Nemolizumab: An antibody that targets the IL-31 receptor alpha. This medication is approved for prurigo nodularis and atopic dermatitis (in adults and pediatric patients aged 12 or older) when used with other therapies.[68][69]

• IL-36R pathway

  • Spesolimab: A humanized monoclonal antibody that acts as a selective antagonist of the IL-36 receptor. This medication is approved for generalized pustular psoriasis flares.[70]

Other Issues

In addition to therapeutic challenges, several areas remain incompletely understood. Many interleukins, particularly IL-29 through IL-38, have undefined biological roles and unclear therapeutic implications.[1][4] However, recent discoveries targeting IL-31 (nemolizumab) and IL-36 (spesolimab) have contributed to progress. Genetic polymorphisms within interleukin genes influence susceptibility to autoimmune and inflammatory diseases, suggesting a role in personalized medicine.[14] The use of cytokine profiles for endotyping conditions such as asthma, atopic dermatitis, and inflammatory bowel disease represents an emerging approach to stratify patients for precision therapy.[2]

Beyond IL-29 through IL-38, cytokines such as IL-39 and IL-40 have been recently proposed but remain incompletely defined. IL-39, a heterodimer composed of IL-23p19 and EBI3, has been implicated in experimental models of lupus-like disease and colitis by promoting Th17 responses and B-cell activation. Yet, its existence and physiological relevance in humans remain controversial.[71][72] IL-40 has been associated with B-cell homeostasis and chronic inflammatory conditions such as rheumatoid arthritis and inflammatory bowel disease, though its precise function and therapeutic implications are still under investigation.[73] Further research is required before these cytokines can be integrated into the established framework of interleukins.

Looking ahead, engineered cytokines, such as IL-2 muteins, are being developed to selectively expand regulatory T cells and reduce toxicity.[6] Research into combination biologic strategies and the use of IL-7 and IL-15 as vaccine adjuvants further reflects the future potential of interleukin-based interventions.[15]

FDA-Issued Box Warnings

• Aldesleukin: Capillary leak syndrome, including life-threatening reactions, has occurred in patients treated with aldesleukin. The drug is contraindicated in patients with severe cardiac, pulmonary, renal, or hepatic impairment. Proleukin should be administered in a hospital with an intensive care unit. Neuropoxicity, such as permanent neurological deficits or coma, has occurred in patients treated with aldesleukin. Treatment should be withheld or discontinued in such cases. Serious infections such as sepsis and bacterial endocarditis have been reported. Active bacterial infections should be treated before starting aldesleukin and stopped or withheld as advised.

• Brodalumab: This drug carries an FDA-issued box warning for suicidal ideation and behavior.[56] Therefore, broadalumab is available only through the Risk Evaluation and Mitigation Strategy program. However, a 6-year pharmacovigilance study reported no new suicide attempts in year 6 and no completed suicides during the entire 6-year period in the United States.[74] Additional studies and vigilance are required.

• Tocilizumab: Tocilizumab increases the risk of serious infections that may lead to hospitalization or death. These infections include tuberculosis, which may be active with pulmonary or extrapulmonary disease, or latent, requiring testing before therapy and treatment if positive. Additionally, tocilizumab increases the risk of invasive fungal infections such as candidiasis, aspergillosis, and pneumocystis. Bacterial, viral, and other opportunistic infections have also been reported. Patients should be monitored during and after treatment for signs and symptoms of infection. If a severe infection develops, tocilizumab should be stopped until the infection is controlled.[75] 

• Sarilumab: Similar to tocilizumab, sarilumab increases the risk of serious infections that may lead to hospitalization or death, including tuberculosis (active pulmonary or extrapulmonary disease). Patients should be tested for latent tuberculosis before use. Invasive fungal infections, such as candidiasis and pneumocystis, may present with disseminated disease, as well as bacterial, viral, and other opportunistic infections. Patients should be closely monitored during therapy, and sarilumab should be interrupted if a severe infection develops. Most patients who developed infections were taking concomitant immunosuppressants such as corticosteroids or methotrexate.

• Reslizumab: Reslizumab carries a warning for anaphylaxis. Treatment should be discontinued immediately if signs or symptoms of anaphylaxis occur.[76]

Enhancing Healthcare Team Outcomes

Optimal use of interleukin-based therapies requires a coordinated, multidisciplinary approach. Clinicians and advanced practitioners are responsible for patient selection, stratifying risk, and tailoring biologic therapy to the clinical context.[2] Pharmacists ensure safe prescribing, screen for drug interactions, and provide counseling on biologic handling and administration.[11] Nurses reinforce adherence, teach self-injection techniques, and monitor for early signs of adverse effects.[13] Infectious disease specialists may be consulted to perform tuberculosis or viral reactivation screening before initiating IL-targeted therapies. In contrast, laboratory professionals provide timely biomarker data such as C-reactive protein, IL-6, or soluble IL-2 receptor to guide clinical decision-making.[17] A gastroenterologist should be consulted for the use of biologics in the treatment of ulcerative colitis or eosinophilic esophagitis.[50] Immunologists and rheumatologists should collaborate in the management of complex disorders, such as Castleman disease.[77][78][79]

Ethical responsibilities include obtaining informed consent, discussing risks such as opportunistic infections, ensuring vaccination status, and maintaining transparency regarding therapeutic costs and accessibility. Interprofessional communication and care coordination are critical: effective information sharing among clinicians, pharmacists, nurses, and laboratory teams helps reduce errors, improve patient safety, and fosters trust.[1] By prioritizing patient-centered care, reinforcing adherence, and integrating timely monitoring, healthcare teams can optimize clinical outcomes and enhance overall team performance in the management of interleukin-directed therapies.[2] An interprofessional approach and open communication among primary care physicians, advanced practice providers, immunologists, rheumatologists, gastroenterologists, nurses, and pharmacists are essential to optimize patient outcomes related to interleukin-based therapies.

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Disclosure: Aziza Harris declares no relevant financial relationships with ineligible companies.

Disclosure: Preeti Patel declares no relevant financial relationships with ineligible companies.