Introduction

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.[1]

General Properties of Cytokines/Interleukins

• Cytokines are proteins made in response to pathogens and other antigens that regulate and mediate inflammatory and immune responses.
• Interleukin production is a self-limited process. The messenger RNA encoding most interleukins is unstable and causes a transient synthesis. These molecules are rapidly secreted once synthesized.
• Cellular responses to interleukins include up- and down-regulatory mechanisms with the induction and participation of genes that encode inhibitors of the cytokine receptors. 
• Interleukins have redundant functions. For instance, IL-4, IL-5, and IL-13 are B-cell growth factors and stimulate B-cell differentiation.
• Cytokines stimulate switching of antibody isotypes in B cells, differentiation of helper T cells into Th-1 and Th-2 subsets, and activation of microbicidal mechanisms in phagocytes.
• Interleukins often influence other interleukin synthesis and actions. For instance, IL-1 promotes lymphocyte activation that leads to the release of IL-2.
• Cellular responses to cytokines are stimulated and regulated by external signals or high-affinity receptors. For example, stimulation of B-cells by pathogens leads to increased expression of cytokine receptors.
• Most cytokines act either on the same cell that secretes the cytokine, for instance, IL-2 produced by T cells operates on the same T cells that made it or on a nearby cell. Besides, cytokines may enter the circulation and act far from the site of production, for example, IL-1 is an endogenous pyrogen that works on the central nervous system (CNS) and causes fever.
• Small quantities of a cytokine are needed to occupy receptors and elicit biologic effects.

Function

Interleukin-1 (IL-1)

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.[2][3][4][5]

Interleukin-2 (IL-2)

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.[6][7]

Interleukin-3 (IL-3)

T cells and stem cells make IL-3. It functions as a multilineage colony-stimulating factor.[8][9]

Interleukin-4 (IL-4)

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.[7]

Interleukin-5 (IL-5)

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.[1]

Interleukin-6 (IL-6)

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.[1][10][1]

Interleukin-7 (IL-7)

Bone marrow stromal cells produce IL-7 that acts on pre-B cells and T cells. It causes B-cell and T-cell proliferation.[11]

Interleukin-8 (IL-8)

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.[12]

Interleukin-9 (IL-9)  

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.[13]

Interleukin-10 (IL-10)

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.[14][15]

Interleukin-11 (IL-11)

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.[16]

Interleukin-12 (IL-12)

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.[16]

Interleukin-13 (IL-13)

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.[17]

Interleukin-14 (IL-14)

T cells produce IL-14, and its principal effects are stimulation of activated B cell proliferation and inhibition of immunoglobulin secretion.

Interleukin-15 (IL-15)

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.

Interleukin-16 (IL-16)

Eosinophils and CD8+T cells synthesize IL-16. Its principal target is CD4+ T cells. It causes CD4+ T cell chemoattraction.

Interleukin-17 (IL-17)

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.[18][19]

Interleukin-18 (IL-18)

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.

Interleukin-19 (IL-19)

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.[20]

Interleukin-20 (IL-20)

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.

Interleukin-21 (IL-21)

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.[21]

Interleukin-22 (IL-22)

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.[22]

Interleukin-23 (IL-23)

Macrophages and dendritic cells mainly synthesize IL-23. It acts on T cells causing maintenance of IL-17 producing T cells.[19]

Interleukin-24 (IL-24)

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.[23] 

Interleukin-25 (IL-25)

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.[24]

Interleukin-26 (IL-26)

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.

Interleukin-27 (IL-27)

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.[10]

Interleukin-28 (IL-28)

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.

Interleukin-29 (IL-29)

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.

Interleukin-30 (IL-30)

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.[10]

Interleukin-31 (IL-31)

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.

Interleukin-32 (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.[25]

Interleukin-33 (IL-33)

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.

Interleukin-34 (IL-34)

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.[26]

Interleukin-35 (IL-35)

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.

Interleukin-36 (IL-36)

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.  

Interleukin-37 (IL-37)

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.

Interleukin-38 (IL-38)

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.[27]

Interleukin (IL-39)

B lymphocytes mainly produce IL-39. It acts on neutrophils inducing their differentiation or expansion.[28]

Interleukin-40 (IL-40)

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.[29]

Clinical Significance

Clinical significance of some cytokines are listed below:[1][28][29][30]

• IL-1 acts on the hypothalamus to induce fever and is therefore called an endogenous pyrogen. It operates on hepatocytes to increase synthesis of specific serum proteins, such as amyloid A protein and fibrinogen. It causes fall in blood pressure or shock in large amounts. Corticosteroids inhibit the IL-1 effect.
• Gene knockout mouse studies have provided evidence that the primary IL-2 function in vivo is the suppression of T responses. Mice lacking IL-2 or its receptor (CD25) develop lymphadenopathy and T cell-mediated autoimmunity.
• Knockout mice lacking IL-10 develop inflammatory bowel disease, probably because of uncontrolled activation of macrophages reacting to enteric microbes. 
• IL-12 overproduction causes allergic disorders. Corticosteroids inhibit the effects of IL-12.
• IL-19 may be used to induce angiogenesis in ischemic tissue.
• The administration of IL-21 may be considered for use as a preventive and therapeutic approach when dealing with Th2-mediated allergic diseases.
• IL-26 shows high expression in psoriatic skin lesions, colonic lesions from individuals with inflammatory bowel disease and synovia of individuals with rheumatoid arthritis. It may constitute a promising target to treat chronic inflammatory disorders.
• IL-27 was found to exerts anti-inflammatory effects in several experimental autoimmune models. IL-27 treatment suppressed autoimmune diabetes.  
• IL-28 may be sufficient treatment of HCV patients.
• IL-29 is a marker of osteoarthritis as joint inflammation implicates it.
• IL-36 also seems to play a significant role in human psoriasis. In psoriatic lesion tissues, IL-36 levels were found to be elevated, and generalized pustular psoriasis was also discovered, which is rare and life-threatening. 
• In lupus patients were elevated IL-37 levels in comparison with healthy controls, and mucocutaneous and renal involvement was correlated with high disease activity.
• Recent studies point to an association between IL-38 and autoimmune diseases. Its role in carcinogenesis or cancer growth is unclear.  
• IL-39 secreted by activated B cells may be a critical pro-inflammatory cytokine and a potential therapeutic target for the treatment of autoimmune diseases such as systemic lupus erythematosus.
• IL-40 expression in several human B-cell lymphomas suggests that it may play a role in the pathogenesis of these diseases.

Other Issues

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.

Enhancing Healthcare Team Outcomes

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.  

Review Questions

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Disclosure: Angel Justiz Vaillant declares no relevant financial relationships with ineligible companies.

Disclosure: Ahmad Qurie declares no relevant financial relationships with ineligible companies.