Interleukins (IL) are a type of cytokine first thought to be expressed by leukocytes alone but have later been found to be produced by many other body cells. They play essential roles in the activation and differentiation of immune cells, as well as proliferation, maturation, migration, and adhesion. They also have pro-inflammatory and anti-inflammatory properties. The primary function of interleukins is, therefore, to modulate growth, differentiation, and activation during inflammatory and immune responses. Interleukins consist of a large group of proteins that can elicit many reactions in cells and tissues by binding to high-affinity receptors in cell surfaces. They have both paracrine and autocrine function. Interleukins are also used in animal studies to investigate aspect related to clinical medicine.
Macrophages, large granular lymphocytes, B cells, endothelium, fibroblasts, and astrocytes secrete IL-1. T cells, B cells, macrophages, endothelium and tissue cells are the principal targets. IL-1 causes lymphocyte activation, macrophage stimulation, increased leukocyte/endothelial adhesion, fever due to hypothalamus stimulation, and release of acute phase proteins by the liver. It may also cause apoptosis in many cell types and cachexia.
T cells produce IL-2. The principal targets are T cells. Its primary effects are T-cell proliferation and differentiation, increased cytokine synthesis, potentiating Fas-mediated apoptosis, and promoting regulatory T cell development. It causes proliferation and activation of NK cells and B-cell proliferation and antibody synthesis. Also, it stimulates the activation of cytotoxic lymphocytes and macrophages.
CD4+T cells (Th2) synthesize IL-4, and it acts on both B and T cells. It is a B-cell growth factor and causes IgE and IgG1 isotype selection. It causes Th2 differentiation and proliferation, and it inhibits IFN gamma-mediated activation on macrophages. It promotes mast cell proliferation in vivo.
CD4+T cells (Th2) produce IL-5, and its principal targets are B cells. It causes B-cell growth factor and differentiation and IgA selection. Besides, causes eosinophil activation and increased production of these innate immune cells.
T and B lymphocytes, fibroblasts and macrophages make IL-6. B lymphocytes and hepatocytes are its principal targets. IL-6 primary effects include B-cell differentiation and stimulation of acute phase proteins.
Bone marrow stromal cells produce IL-7 that acts on pre-B cells and T cells. It causes B-cell and T-cell proliferation.
Monocytes and fibroblasts make IL-8. Its principal targets are neutrophils, basophils, mast cells, macrophages, and keratinocytes. It causes neutrophil chemotaxis, angiogenesis, superoxide release, and granule release.
Th9, Th2, Th17, mast cells, NKT cells, and regulatory T cells produce this cytokine. It enhances T-cell survival, mast cell activation and synergy with erythropoietin.
Th2 cells produce IL-10. Its principal targets are Th1 cells. It causes inhibition of IL-2 and interferon gamma. It decreases the antigen presentation, and MHC class II expression of dendritic cells, co-stimulatory molecules on macrophages and it also downregulates pathogenic Th17 cell responses. It inhibits IL-12 production by macrophages.
Bone marrow stromal cells and fibroblasts produce IL-11. The IL-11 principal targets are hemopoietic progenitors and osteoclasts. The IL-11 primary effects include osteoclast formation, colony stimulating factor, raised platelet count in vivo, and inhibition of pro-inflammatory cytokine production.
Monocytes produce IL-12. Its principal targets are T cells. It causes induction of Th1 cells. Besides, it is a potent inducer of interferon gamma production by T lymphocytes and NK cells.
CD4+T cells (Th2), NKT cells and mast cells synthesize IL-13. It acts on monocytes, fibroblasts, epithelial cells and B cells. The IL-13 significant effects are B-cell growth and differentiation, stimulates isotype switching to IgE. It causes increased mucus production by epithelial cells, increased collagen synthesis by fibroblasts and inhibits pro-inflammatory cytokine production. Also, IL-13 works together with IL-4 in producing biologic effects associated with allergic inflammation and in defense against parasites.
T cells produce IL-14, and its principal effects are stimulation of activated B cell proliferation and inhibition of immunoglobulin secretion.
Monocytes, epithelium, and muscles make IL-15. It acts on T cells and activated B cells. It causes the proliferation of both B and T cells. It causes NK cell memory and CD8+ T cell proliferation.
Eosinophils and CD8+T cells synthesize IL-16. Its principal target is CD4+ T cells. It causes CD4+ T cell chemoattraction.
This cytokine is produced by Th-17. It acts on epithelial and endothelial cells. IL-17 main effects are the release of IL-6 and other pro-inflammatory cytokines. It enhances the activities of antigen-presenting cells. It stimulates chemokine synthesis by endothelial cells.
Macrophages mostly make IL-18, which can be produced by hepatocytes and keratinocytes. Its principal target is a co-factor in Th1 cell induction. It causes interferon gamma production and enhances NK cell activity.
Th2 lymphocytes synthesize IL-19 and acts on resident vascular cells in addition to immune cells. It is an anti-inflammatory molecule. It promotes immune responses mediated by regulatory lymphocytes and has substantial activity on microvascular.
Immune cells and activated epithelial cells secrete IL-20. It acts on epithelial cells. It plays a vital role in the cellular communication between epithelial cells and the immune system under inflammatory conditions.
NK cells and CD4+ T lymphocytes make IL-21. It acts on various immune cells of innate and the adaptive immune systems. IL-21 promotes B and T lymphocyte proliferation and differentiation. It enhances NK cell activity.
Different cells in both innate and acquired immunities produce IL-22, but the primary sources are T cells. Th22 cell is a new line of CD4+ T cells, which differentiated from naive T cells in the presence of various pro-inflammatory cytokines including IL-6. IL-22 inhibits IL-4 production. It also has essential functions in mucosal surface protection and tissue repair.
Macrophages and dendritic cells mainly synthesize IL-23. It acts on T cells causing maintenance of IL-17 producing T cells.
Monocytes, T and B cells mostly make IL-24. It causes cancer-specific cell death, causes wound healing and protects against bacterial infections and cardiovascular diseases.
Dendritic cells produced predominantly IL-25. It acts on various types of cells, including Th2 cells. It stimulates the synthesis of Th2 cytokine profile including IL-4 and IL-13.
It is strongly associated inflammatory activity with IL-26. Th17 cells produce this interleukin. It acts on epithelial cells and intestinal epithelial cells. It induces IL-10 expression, stimulates the production of IL-1-beta, IL-6, and IL-8 and causes Th17 cell generation.
T cells make IL-27 that activates STAT-1 and STAT-3, which regulates immune responses. IL-27 stimulates IL-10 production. It is a pro-inflammatory molecule and upregulates type-2 interferon synthesis by natural killer cells.
Regulatory T-cells synthesize IL-28, which acts on keratinocytes and melanocytes. It stimulates cell presentation of viral antigens to CD8+T lymphocytes. IL-28 also upregulates TLR-2 and TLR-3 expression. IL-28 enhances the keratinocyte capacity to recognize pathogens in the healthy skin.
IL-29 is a type-3 interferon and produced by virus-infected cells, dendritic cells, and regulatory T-cells. It upregulates viral protective responses. Virus-infected cells may regulate IL-29 genome.
Monocytes mainly produce IL-30 in response to TLR agonists including bacterial LPS. It acts on monocytes, macrophages, dendritic cells, T and B lymphocytes, natural killer cells, mast cells, and endothelial cells.
IL-31 is produced mainly by Th2 cells and dendritic cells. It is a proinflammatory cytokine and a chemotactic factor that direct polymorphonuclear cells, monocytes, and T cells to inflammatory lesions. IL-31 induces chemokines production and synthesis of IL-6, IL-16, and IL-32.
IL-32 is a pro-inflammatory molecule. Natural killer cells and monocytes mainly produce it. IL-32 induces the synthesis of various cytokines including IL-6, and IL-1beta. It inhibits IL-15 production.
Mast cells and Th2 lymphocytes express IL-33 that acts on various innate and immune cells including dendritic cells and T and B lymphocytes. It mediates Th2 responses and therefore participates in the protection against parasites and type-I hypersensitivity reaction.
Various phagocytes and epithelial cells synthesize Interleukin-34 (IL-34). It enhances IL-6 production and participates in the differentiation and development of antigen-presenting cells including microglia.
Regulatory B cells mainly secrete it. One of the primary functions of this interleukin is its involvement in lymphocyte differentiation. It exhibits an immune-suppressive effect.
Phagocytes mainly make IL-36. It acts on T lymphocytes and NK cells regulating the IFN-γ synthesis. It stimulates the hematopoiesis and expression of both MHC class I and II molecules as well as intracellular adhesion molecules (ICAM)-1.
IL-37 plays an essential role in the regulation of the innate immunity causing immunosuppression. Phagocytes and organs including the uterus, testis, and thymus express it. IL-37 upregulates immune responses and inflammation in autoimmune disorders.
Il-38 acts on T cells and inhibits the synthesis of IL-17 and IL-22. The placenta, tonsil's B lymphocytes, spleen, skin, and thymus widely express IL-38.
B lymphocytes mainly produce IL-39. It acts on neutrophils inducing their differentiation or expansion.
IL-40 is produced in the bone marrow, fetal liver, and by activated B cells. IL-40 plays a vital role in the development of humoral immune responses.
Therapy of human diseases with interleukins
In the immunotherapy of melanoma and renal carcinoma have successfully been used interleukin-2 and interferon-gamma. Their mechanisms of action involve the activation of natural killer (NK) cells and T lymphocytes. The FDA has approved these 2 cytokines for the treatment of these 2 malignancies.
The use of interleukins can lead to many clinical manifestations. It is importance that an interprofessional team monitor every patient that is being treated with these molecules. This will prevent for example an anaphylactoid reaction.
|||Interleukins, from 1 to 37, and interferon-γ: receptors, functions, and roles in diseases., Akdis M,Burgler S,Crameri R,Eiwegger T,Fujita H,Gomez E,Klunker S,Meyer N,O'Mahony L,Palomares O,Rhyner C,Ouaked N,Schaffartzik A,Van De Veen W,Zeller S,Zimmermann M,Akdis CA,, The Journal of allergy and clinical immunology, 2011 Mar [PubMed PMID: 21377040]|
|||Bioinformatics analyses of pathways and gene predictions in IL-1α and IL-1β knockout mice with spinal cord injury., Zhu Z,Wang D,Jiao W,Chen G,Cao Y,Zhang Q,Wang J,, Acta histochemica, 2017 Sep [PubMed PMID: 28851482]|
|||Structure-function relationship in the IL-1 family., Boraschi D,Bossu P,Macchia G,Ruggiero P,Tagliabue A,, Frontiers in bioscience : a journal and virtual library, 1996 Oct 1 [PubMed PMID: 9159234]|
|||Interleukin-1 receptor antagonist: role in biology., Arend WP,Malyak M,Guthridge CJ,Gabay C,, Annual review of immunology, 1998 [PubMed PMID: 9597123]|
|||Dinarello CA, Overview of the IL-1 family in innate inflammation and acquired immunity. Immunological reviews. 2018 Jan; [PubMed PMID: 29247995]|
|||Interleukin 2: from immunostimulation to immunoregulation and back again., Bachmann MF,Oxenius A,, EMBO reports, 2007 Dec [PubMed PMID: 18059313]|
|||The role of interleukin (IL)-2 and IL-4 in herpes simplex virus type 1 ocular replication and eye disease., Ghiasi H,Cai S,Slanina SM,Perng GC,Nesburn AB,Wechsler SL,, The Journal of infectious diseases, 1999 May [PubMed PMID: 10191208]|
|||IL-3 in the clinic., Eder M,Geissler G,Ganser A,, Stem cells (Dayton, Ohio), 1997 [PubMed PMID: 9323793]|
|||Interleukin 3: from colony-stimulating factor to pluripotent immunoregulatory cytokine., Frendl G,, International journal of immunopharmacology, 1992 Apr [PubMed PMID: 1618595]|
|||Interleukin (IL)-6 Inhibits IL-27- and IL-30-Mediated Inflammatory Responses in Human Monocytes., Petes C,Mariani MK,Yang Y,Grandvaux N,Gee K,, Frontiers in immunology, 2018 [PubMed PMID: 29497424]|
|||Bellelis P,Frediani Barbeiro D,Gueuvoghlanian-Silva BY,Kalil J,Abrão MS,Podgaec S, Interleukin-15 and Interleukin-7 are the Major Cytokines to Maintain Endometriosis. Gynecologic and obstetric investigation. 2019 Feb 1; [PubMed PMID: 30712043]|
|||Xu Z,Zhou X,Chen G, Expression and Mechanism of Interleukin 1 (IL-1), Interleukin 2 (IL-2), Interleukin 8 (IL-8), BMP, Fibroblast Growth Factor 1 (FGF1), and Insulin-Like Growth Factor (IGF-1) in Lumbar Disc Herniation. Medical science monitor : international medical journal of experimental and clinical research. 2019 Feb 4; [PubMed PMID: 30716059]|
|||Zhou ZJ,Zhang YS,Liang CX,Yang ZY, [Role of Th9, Th17, Treg Cells levels and IL-9, IL-17 and TGF-β Expression in Peripheral Blood of Patients with ITP in Pathogenesis of ITP]. Zhongguo shi yan xue ye xue za zhi. 2019 Feb; [PubMed PMID: 30738467]|
|||Cerebrospinal fluid IL-10 as an early stage discriminative marker between multiple sclerosis and neuro-Behçet disease., Belghith M,Bahrini K,Kchaou M,Maghrebi O,Belal S,Barbouche MR,, Cytokine, 2018 Apr 3 [PubMed PMID: 29625335]|
|||IL-10: the master regulator of immunity to infection., Couper KN,Blount DG,Riley EM,, Journal of immunology (Baltimore, Md. : 1950), 2008 May 1 [PubMed PMID: 18424693]|
|||Jiang T,Huang Z,Zhang S,Zou W,Xiang L,Wu X,Shen Y,Liu W,Zeng Z,Zhao A,Zhou S,Zeng Q, miR‑23b inhibits proliferation of SMMC‑7721 cells by directly targeting IL‑11. Molecular medicine reports. 2018 Aug; [PubMed PMID: 29901200]|
|||Zhang JH,Zhang M,Wang YN,Zhang XY, Correlation between IL-4 and IL-13 gene polymorphisms and asthma in Uygur children in Xinjiang. Experimental and therapeutic medicine. 2019 Feb; [PubMed PMID: 30680016]|
|||IL-17A, IL-17RC polymorphisms and IL17 plasma levels in Tunisian patients with rheumatoid arthritis., Dhaouadi T,Chahbi M,Haouami Y,Sfar I,Abdelmoula L,Ben Abdallah T,Gorgi Y,, PloS one, 2018 [PubMed PMID: 29584788]|
|||Central Role of IL-23 and IL-17 Producing Eosinophils as Immunomodulatory Effector Cells in Acute Pulmonary Aspergillosis and Allergic Asthma., Guerra ES,Lee CK,Specht CA,Yadav B,Huang H,Akalin A,Huh JR,Mueller C,Levitz SM,, PLoS pathogens, 2017 Jan [PubMed PMID: 28095479]|
|||Interleukin-19 can enhance angiogenesis by Macrophage Polarization., Gabunia K,Autieri MV,, Macrophage, 2015 [PubMed PMID: 26029742]|
|||Interleukin-21 suppresses the differentiation and functions of T helper 2 cells., Lin PY,Jen HY,Chiang BL,Sheu F,Chuang YH,, Immunology, 2015 Apr [PubMed PMID: 25351608]|
|||Interleukin-22 in human inflammatory diseases and viral infections., Shabgah AG,Navashenaq JG,Shabgah OG,Mohammadi H,Sahebkar A,, Autoimmunity reviews, 2017 Dec [PubMed PMID: 29037907]|
|||Mechanism of Action and Applications of Interleukin 24 in Immunotherapy., Persaud L,De Jesus D,Brannigan O,Richiez-Paredes M,Huaman J,Alvarado G,Riker L,Mendez G,Dejoie J,Sauane M,, International journal of molecular sciences, 2016 Jun 2 [PubMed PMID: 27271601]|
|||IL-25 and IL-33 Contribute to Development of Eosinophilic Airway Inflammation in Epicutaneously Antigen-Sensitized Mice., Morita H,Arae K,Unno H,Toyama S,Motomura K,Matsuda A,Suto H,Okumura K,Sudo K,Takahashi T,Saito H,Matsumoto K,Nakae S,, PloS one, 2015 [PubMed PMID: 26230091]|
|||Elevated Gene Expression of Interleukin-32 Isoforms Alpha, Beta, Gamma, and Delta in the Peripheral Blood of Chronic Psoriatic Patients., Al-Shobaili HA,Rasheed Z,, Diseases (Basel, Switzerland), 2018 Mar 14 [PubMed PMID: 29538330]|
|||Interleukin-34 sustains pro-tumorigenic signals in colon cancer tissue., Franzè E,Dinallo V,Rizzo A,Di Giovangiulio M,Bevivino G,Stolfi C,Caprioli F,Colantoni A,Ortenzi A,Grazia AD,Sica G,Sileri PP,Rossi P,Monteleone G,, Oncotarget, 2018 Jan 9 [PubMed PMID: 29423057]|
|||Clinical implications of the novel cytokine IL-38 expressed in lung adenocarcinoma: Possible association with PD-L1 expression., Takada K,Okamoto T,Tominaga M,Teraishi K,Akamine T,Takamori S,Katsura M,Toyokawa G,Shoji F,Okamoto M,Oda Y,Hoshino T,Maehara Y,, PloS one, 2017 [PubMed PMID: 28727766]|
|||A novel IL-23p19/Ebi3 (IL-39) cytokine mediates inflammation in Lupus-like mice., Wang X,Wei Y,Xiao H,Liu X,Zhang Y,Han G,Chen G,Hou C,Ma N,Shen B,Li Y,Egwuagu CE,Wang R,, European journal of immunology, 2016 Jun [PubMed PMID: 27019190]|
|||Identification of IL-40, a Novel B Cell-Associated Cytokine., Catalan-Dibene J,Vazquez MI,Luu VP,Nuccio SP,Karimzadeh A,Kastenschmidt JM,Villalta SA,Ushach I,Pone EJ,Casali P,Raffatellu M,Burkhardt AM,Hernandez-Ruiz M,Heller G,Hevezi PA,Zlotnik A,, Journal of immunology (Baltimore, Md. : 1950), 2017 Nov 1 [PubMed PMID: 28978694]|
|||Li Y,Yao L,Liu S,Wu J,Xia L,Shen H,Lu J, Elevated serum IL-35 levels in rheumatoid arthritis are associated with disease activity. Journal of investigative medicine : the official publication of the American Federation for Clinical Research. 2019 Jan 18 [PubMed PMID: 30659089]|