Welcome to part 4 of the ODX Inflammation Series. In this post, the ODX Research Team reviews cytokines, their sources and their functions.
A wide variety of cells produce cytokines, including fibroblasts, nerve, mast, glial, adipose, and endothelial cells, though macrophages and helper T (Th) lymphocytes are the primary producers.[1]
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Cytokine |
Family |
Main sources |
Function |
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IL-1β |
IL-1 |
Macrophages, monocytes |
Pro-inflammation, proliferation, apoptosis, differentiation |
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IL-4 |
IL-4 |
Th-cells |
Anti-inflammation, T-cell and B-cell proliferation, B-cell differentiation |
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IL-6 |
IL-6 |
Macrophages, T-cells, adipocyte |
Pro-inflammation, differentiation, cytokine production |
|
IL-8 |
CXC |
Macrophages, epithelial cells, endothelial cells |
Pro-inflammation, chemotaxis, angiogenesis |
|
IL-10 |
IL-10 |
Monocytes, T-cells, B-cells |
Anti-inflammation, inhibition of the pro-inflammatory cytokines |
|
IL-12 |
IL-12 |
Dendritic cells, macrophages, neutrophils |
Pro-inflammation, cell differentiation, activates NK cell |
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IL-11 |
IL-6 |
Fibroblasts, neurons, epithelial cells |
Anti-inflammation, differentiation, induces acute phase protein |
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TNF-α |
TNF |
Macrophages, NK cells, CD4+lymphocytes, adipocyte |
Pro-inflammation, cytokine production, cell proliferation, apoptosis, anti-infection |
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IFN-γ
|
INF |
T-cells, NK cells, NKT cells |
Pro-inflammation, innate, adaptive immunity anti-viral |
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GM-CSF |
IL-4 |
T-cells, macrophages, fibroblasts
|
Pro-inflammation, macrophage activation, increase neutrophil and monocyte function |
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TGF-β |
TGF
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Macrophages, T cells |
Anti-inflammation, inhibition of pro-inflammatory cytokine production |
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Interleukin-1 (IL-1)
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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. 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. |
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Interleukin-2 (IL-2)
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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 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. |
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Interleukin-3 (IL-3) |
T cells and stem cells make IL-3. It functions as a multilineage colony-stimulating factor. |
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Interleukin-4 (IL-4)
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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. |
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Interleukin-5 (IL-5)
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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. |
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Interleukin-6 (IL-6)
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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. |
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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. |
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Interleukin-8 (IL-8)
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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. |
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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. |
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Interleukin-10 (IL-10)
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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. Knockout mice lacking IL-10 develop inflammatory bowel disease, probably because of uncontrolled activation of macrophages reacting to enteric microbes. |
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Interleukin-11 (IL-11)
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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. |
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Interleukin-12 (IL-12)
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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. IL-12 overproduction causes allergic disorders. Corticosteroids inhibit the effects of IL-12. |
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Interleukin-13 (IL-13)
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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. |
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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. |
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Interleukin-15 (IL-15)
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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. |
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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. |
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Interleukin-17 (IL-17)
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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. |
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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. |
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Interleukin-19 (IL-19)
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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. IL-19 may be used to induce angiogenesis in ischemic tissue. |
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Interleukin-20 (IL-20)
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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. |
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Interleukin-21 (IL-21)
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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. The administration of IL-21 may be considered for use as a preventive and therapeutic approach when dealing with Th2-mediated allergic diseases. |
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Interleukin-22 (IL-22)
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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. |
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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. |
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Interleukin-24 (IL-24)
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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. |
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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. |
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Interleukin-26 (IL-26)
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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. 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. |
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Interleukin-27 (IL-27)
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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. IL-27 was found to exerts anti-inflammatory effects in several experimental autoimmune models. IL-27 treatment suppressed autoimmune diabetes. |
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Interleukin-28 (IL-28)
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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-28 may be sufficient treatment of HCV patients. |
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Interleukin-29 (IL-29)
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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. IL-29 is a marker of osteoarthritis as joint inflammation implicates it. |
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Interleukin-30 (IL-30)
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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. |
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Interleukin-31 (IL-31)
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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. |
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Interleukin-32 (IL-32)
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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. |
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Interleukin-33 (IL-33)
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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. |
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Interleukin-34 (IL-34)
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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. |
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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. |
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Interleukin-36 (IL-36)
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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-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. |
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Interleukin-37 (IL-37)
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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. In lupus patients were elevated IL-37 levels in comparison with healthy controls, and mucocutaneous and renal involvement was correlated with high disease activity. |
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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. Recent studies point to an association between IL-38 and autoimmune diseases. Its role in carcinogenesis or cancer growth is unclear. |
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Interleukin (IL-39)
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B lymphocytes mainly produce IL-39. It acts on neutrophils inducing their differentiation or expansion. 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. |
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Interleukin-40 (IL-40)
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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. IL-40 expression in several human B-cell lymphomas suggests that it may play a role in the pathogenesis of these diseases. |
Ultimately, cytokines are complex in that they can be produced by and have effects on a variety of tissues. They can have pro- and anti-inflammatory effects; can work together to upregulate or downregulate other cytokines, and some may exert both pro- and anti-inflammatory effects depending on signaling pathways: [4]
Next Up: Inflammation Part 5 - The Cytokine Storm
[1] Zhang, Jun-Ming, and Jianxiong An. “Cytokines, inflammation, and pain.” International anesthesiology clinics vol. 45,2 (2007): 27-37.
[2] Chen, Linlin et al. “Inflammatory responses and inflammation-associated diseases in organs.” Oncotarget vol. 9,6 7204-7218. 14 Dec. 2017.
[3] Justiz Vaillant, Angel A. and Ahmad Qurie. “Interleukin.” StatPearls, StatPearls Publishing, 30 August 2020.
[4] Monastero, Rebecca N, and Srinivas Pentyala. “Cytokines as Biomarkers and Their Respective Clinical Cutoff Levels.” International journal of inflammation vol. 2017 (2017): 4309485.