Interleukins

Interleukins are a type of cytokines (signaling proteins) that communicate messages between different parts of the immune system. The majority of interleukins are synthesized by helper CD4 T lymphocytes along with other cells such as monocytes, macrophages, and endothelial cells. Interleukins underlie the development and differentiation of T and B lymphocytes and hematopoietic cells.

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Origin and Function of Interleukins

  • The term interleukin is derived from:
    • “Inter,” which means between or among
    • “Leukin,” which is the origin of the word “leukocyte”
    • Together, the word interleukin refers to a molecule that plays a role in communication between the cellular constituents of the immune system.
    • The primary function of ILs is to modulate the growth, differentiation, and activation of immune cells during inflammatory and immune responses.
    • ILs play a role in both innate and adaptive immune responses.
  • ILs are produced in response to:
    • Pathogens
    • Self-antigens
    • Other ILs
  • ILs influence the synthesis and actions of other ILs (e.g., IL-1 stimulates IL-2 release).
  • Only very small quantities of ILs are needed to occupy receptors and elicit biological effects.
  • ILs are a diverse group of molecules with differing protein structures.
  • Approximately 35 ILs have been identified and described.
Table: Interleukins and their effects on target cells
NameSourceTarget cellsEffect on target cells
IL-1
  • Macrophages and monocytes
  • B cells
  • Dendritic cells
  • Endothelial cells
  • Fibroblasts
  • Astrocytes
  • T helper cells
  • B cells
  • Macrophages
  • Endothelium
  • Inflammatory
  • Induces maturation, activation, and proliferation of lymphocytes
  • Pyrogenic
  • Promotes secretion of cytokines and acute-phase proteins
  • Increases leukocyte-endothelial adhesion
IL-2T cells
  • T cells
  • B cells
  • NK cells
  • Macrophages
  • Stimulates growth and differentiation of T cells
  • Prevents development of T cells that attack self-antigens
IL-3T cells
  • Hematopoietic stem cells
  • Macrophages
  • Mast cells
  • Differentiation and proliferation of myeloid progenitor cells to erythrocytes and granulocytes
  • Histamine release
IL-4
  • Th2 cells
  • Mast cells
  • T cells
  • B cells
  • Macrophages
  • Differentiation of T cells into Th2 cells
  • B cell growth factor
  • IgG1 and IgE production
IL-5Th2 cells
  • B cells
  • Eosinophils
  • B cell growth and differentiation
  • IgA production
  • Eosinophil growth, differentiation, and activation
IL-6
  • Macrophages
  • T cells
  • B cells
  • Astrocytes
  • Fibroblasts
  • Endothelial cells
  • B cells
  • Hematopoietic stem cells
  • T cells
  • Differentiation of B and T cells
  • Differentiation and proliferation of stem and progenitor cells
  • Antibody secretion
  • Pyrogenic
  • Acute-phase protein synthesis
IL-7
  • Bone marrow stromal cells
  • Thymus stromal cells
  • Pre-B cells
  • Pre-T cells
Differentiation and proliferation of lymphoid progenitor cells
IL-8
  • T cells
  • Macrophages
  • Fibroblasts
  • Neutrophils
  • Basophils
  • Mast cells
  • Macrophages
  • Keratinocytes
  • Neutrophil chemotaxis
  • Granule release
  • Angiogenesis
IL-9
  • T cells
  • Mast cells
  • NK cells
  • T cells
  • Mast cells
  • T cell survival and cytokine secretion
  • Mast cell growth and activation
IL-10
  • Th2 cells
  • Mast cells
  • Macrophages
  • B cells
  • Macrophages
  • B cells
  • Th1 cells
  • Dendritic cells
  • Inhibits Th1 cytokine production (IFN-γ, TNF-β, IL-2)
  • Inhibits macrophage IL-12 production
  • Decreases MHC class II expression on dendritic cells
IL-11
  • Bone marrow stromal cells
  • Fibroblasts
  • Hematopoietic progenitor cells
  • Osteoclasts
  • Acute-phase protein production
  • Osteoclast formation
IL-12
  • Dendritic cells
  • B cells
  • T cells
  • Macrophages
  • Neutrophils
  • T cells
  • NK cells
  • Differentiation into Th1 cells
  • Induces IFN-γ production
IL-13
  • Th2 cells
  • Mast cells
  • NK cells
  • B cells
  • Monocytes
  • Fibroblasts
  • Epithelial cells
  • Growth and differentiation of B cells
  • IgE production
  • Increased mucus production
  • Collagen synthesis
  • Inhibits production of pro-inflammatory cytokines
IL-14T cellsB cells
  • Growth and proliferation of B cells
  • Inhibits Ig secretion
IL-15
  • Monocytes
  • Epithelial cells
  • T cells
  • B cells
  • B and T cell proliferation
  • Induces production of NK cells
IL-16
  • Eosinophils
  • T cells
CD4+ T cellsCD4+ chemoattraction
IL-17Th-17 cells
  • Epithelium
  • Endothelium
  • Inflammatory cytokine release (including IL-6)
  • Angiogenesis
IL-18Macrophages
  • Th1 cells
  • NK cells
  • Production of IFN-γ
  • Enhances NK cell activity
IL-19Th2 cells
  • Macrophages
  • T cells
  • B cells
Anti-inflammatory
IL-20
  • Monocytes
  • Epithelial cells
Epithelial cells
  • Cellular communication between epithelial cells
  • Wound healing and tissue repair
IL-21
  • CD4+ T cells
  • NK cells
All lymphocytes
  • B and T cell proliferation and differentiation
  • Enhances NK cell activity
IL-22T cellsEpithelial cells
  • Inhibits IL-4 production
  • Tissue repair
  • Protection of mucosal surfaces
IL-23
  • Macrophages
  • Dendritic cells
T cellsMaintenance of IL-17 producing cells
IL-24
  • Monocytes
  • T cells
  • B cells
  • Tumor suppression
  • Wound healing
IL-25
  • T cells
  • Mast cells
  • Eosinophils
  • Macrophages
  • Epithelial cells
  • Induces the production of IL-4, IL-5, and IL-13
  • Increases production of antibodies
  • Activates eosinophils
IL-26T cellsInduces secretion of IL-10 and IL-8
IL-27
  • Macrophages
  • Dendritic cells
Upregulation of proinflammatory cytokines
IL-28
  • Dendritic cells
  • T cells
Plays a role in immune defense against viruses
IL-29
  • Dendritic cells
  • T cells
Plays a role in immune defense against microbes
IL-30
  • Monocytes
  • Cancer cells (possibly)
May play a role in tumor growth
IL-31
  • Th2 cells
  • Dendritic cells
  • May play a role in inflammation of the skin
  • Induces cytokine and chemokine production
IL-32
  • Monocytes
  • NK cells
Induces cytokine and chemokine production
IL-33
  • Macrophages
  • Dendritic cells
  • Epithelial cells
  • Activates Th2 immune response
  • Mast cell and basophil activation
IL-34
  • Monocytes
  • Macrophages
  • Microglia
Differentiation, migration, and survival of antigen-presenting cells
IL-35
  • Regulatory T cells
  • B cells
  • Lymphocyte differentiation
  • Immune suppression
IL-36Macrophages
  • Regulates IFN-γ synthesis
  • Stimulates MHC expression
NK: natural killer
TNF: tumor necrosis factor
Th: T helper
IFN: interferon

Clinically Relevant Interleukins

Interleukin-2

  • Important for stimulating T helper (Th)1 immune response:
    • Fights intracellular pathogens (e.g., viruses)
    • Important for tumor surveillance
    • Becomes overactive in autoimmune conditions
  • Can be administered pharmacologically:
    • Uses: 
      • Immunotherapy to treat patients with cancer (melanoma and renal carcinoma)
      • Has been used in clinical trials to increase CD4 counts in patients who are HIV positive
    • Adverse effects:
      • Fever
      • Fatigue
      • Confusion
      • GI upset
      • Arrhythmia

Interleukin-4 and IL-5

  • Together, IL-4 and IL-5 play an important role in IgE-mediated allergic responses.
  • IL-4:
    • Stimulates IgE synthesis
    • Increases the adherence and passage of lymphocytes through the endothelium
  • IL-5 stimulates eosinophil production.
  • Medical targets: Dupilumab is a monoclonal antibody that targets the IL-4 receptor; it has been approved by the FDA to treat asthma and atopic dermatitis.

Interleukin-6

  • Acute-phase reactant 
  • Produced by the liver in response to infection or physiologic stress
  • Stimulates innate and adaptive immune responses

Interleukin-12, IL-17, and IL-23

  • Play an important role in the pathogenesis of psoriasis
  • Targets of monoclonal antibodies used to treat psoriasis

References

  1. Akdis, M., et al. (2011). Interleukins, from 1 to 37, and interferon-γ: Receptors, functions, and roles in diseases. J Allergy Clin Immunol. 127(3), 701-21.e1–70. https://pubmed.ncbi.nlm.nih.gov/21377040/
  2. Zhu, Z., et al. (2017). Bioinformatics analyses of pathways and gene predictions in IL-1α and IL-1β knockout mice with spinal cord injury. Acta Histochem. 119(7), 663–670. https://pubmed.ncbi.nlm.nih.gov/28851482/
  3. Boraschi, D., et al. (1996). Structure-function relationship in the IL-1 family. Front Biosci. 1, d270–308. https://pubmed.ncbi.nlm.nih.gov/9159234/
  4. Arend, W.P., et al. (1998). Interleukin-1 receptor antagonist: Role in biology. Annu Rev Immunol. 16, 27–55. https://pubmed.ncbi.nlm.nih.gov/9597123/
  5. Dinarello, C.A. (2018). Overview of the IL-1 family in innate inflammation and acquired immunity. Immunol Rev. 281(1), 8–27. https://pubmed.ncbi.nlm.nih.gov/29247995/
  6. Bachmann, M.F., Oxenius, A. (2007). Interleukin 2: From immunostimulation to immunoregulation and back again. EMBO Rep. 8(12), 1142–1148. https://pubmed.ncbi.nlm.nih.gov/18059313/
  7. Ghiasi, H., et al. (1999). The role of interleukin (IL)-2 and IL-4 in herpes simplex virus type 1 ocular replication and eye disease. J Infect Dis. 179(5), 1086–1093. https://pubmed.ncbi.nlm.nih.gov/10191208/
  8. Eder, M., Geissler, G., Ganser, A. (1997). IL-3 in the clinic. Stem Cells. 15(5), 327–333. https://pubmed.ncbi.nlm.nih.gov/9323793/
  9. Frendl, G. (1992). Interleukin 3: From colony-stimulating factor to pluripotent immunoregulatory cytokine. Int J Immunopharmacol. 14(3), 421–430. https://pubmed.ncbi.nlm.nih.gov/1618595/
  10. Belghith, M., et al. (2018). Cerebrospinal fluid IL-10 as an early stage discriminative marker between multiple sclerosis and neuro-Behçet disease. Cytokine. 108, 160–167. https://pubmed.ncbi.nlm.nih.gov/29625335/
  11. Couper, K.N., Blount, D.G., Riley, E.M. (2008). IL-10: The master regulator of immunity to infection. J Immunol. 180(9), 5771–5777. https://pubmed.ncbi.nlm.nih.gov/18424693/
  12. Jiang, T., et al. (2018). miR‑23b inhibits proliferation of SMMC‑7721 cells by directly targeting IL‑11. Mol Med Rep. 18(2), 1591–1599. https://pubmed.ncbi.nlm.nih.gov/29901200/
  13. Zhang, J.H., et al. (2019). Correlation between IL-4 and IL-13 gene polymorphisms and asthma in Uygur children in Xinjiang. Exp Ther Med. 17(2), 1374–1382. https://pubmed.ncbi.nlm.nih.gov/30680016/
  14. Dhaouadi, T., et al. (2018). IL-17A, IL-17RC polymorphisms and IL17 plasma levels in Tunisian patients with rheumatoid arthritis. PLoS One. 13(3), e0194883. https://pubmed.ncbi.nlm.nih.gov/29584788/
  15. Guerra, E.S., et al. (2017). Central role of IL-23 and IL-17 producing eosinophils as immunomodulatory effector cells in acute pulmonary aspergillosis and allergic asthma. PLoS Pathog. 13(1), e1006175. https://pubmed.ncbi.nlm.nih.gov/28095479/
  16. Gabunia, K., Autieri, M.V. (2015). Interleukin-19 can enhance angiogenesis by macrophage polarization. Macrophage (Houst). 2(1), e562. https://pubmed.ncbi.nlm.nih.gov/26029742/
  17. Lin, P.Y., et al. (2015). Interleukin-21 suppresses the differentiation and functions of T helper 2 cells. Immunology. 144(4), 668–676. https://pubmed.ncbi.nlm.nih.gov/25351608/
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