Interleukin 4 Explained

Symbol:	IL4
Interleukin 4
Pfam:	PF00727
Pfam Clan:	CL0053
Interpro:	IPR002354
Prosite:	PDOC00655
Scop:	2int

The interleukin 4 (IL4, IL-4) is a cytokine that induces differentiation of naive helper T cells (T_h0 cells) to T_h2 cells. Upon activation by IL-4, T_h2 cells subsequently produce additional IL-4 in a positive feedback loop. IL-4 is produced primarily by mast cells, T_h2 cells, eosinophils and basophils.^[1] It is closely related and has functions similar to IL-13.

Function

Interleukin 4 has many biological roles, including the stimulation of activated B cell and T cell proliferation, and the differentiation of B cells into plasma cells. It is a key regulator in humoral and adaptive immunity. IL-4 induces B cell class switching to IgE, and up-regulates MHC class II production. IL-4 decreases the production of T_h1 cells, macrophages, IFNγ, and dendritic cells IL-12.

Overproduction of IL-4 is associated with allergies.^[2]

Inflammation and wound repair

Tissue macrophages play an important role in chronic inflammation and wound repair. The presence of IL-4 in extravascular tissues promotes alternative activation of macrophages into M2 cells and inhibits classical activation of macrophages into M1 cells. An increase in repair macrophages (M2) is coupled with secretion of IL-10 and TGF-β that result in a diminution of pathological inflammation. Release of arginase, proline, polyaminases and TGF-β by the activated M2 cell is tied with wound repair and fibrosis.^[3]

Receptor

The receptor for interleukin-4 is known as the IL-4Rα. This receptor exists in 3 different complexes throughout the body. Type 1 receptors are composed of the IL-4Rα subunit with a common γ chain and specifically bind IL-4. Type 2 receptors consist of an IL-4Rα subunit bound to a different subunit known as IL-13Rα1. These type 2 receptors have the ability to bind both IL-4 and IL-13, two cytokines with closely related biological functions.^{[4] [5]}

Structure

IL-4 has a compact, globular fold (similar to other cytokines), stabilised by 3 disulphide bonds.^[6] One half of the structure is dominated by a 4 alpha-helix bundle with a left-handed twist.^[7] The helices are anti-parallel, with 2 overhand connections, which fall into a 2-stranded anti-parallel beta-sheet.

Evolution

IL-4 is closely related to IL-13, and both stimulate type 2 immunity.^[8] Genes of this family have also been found in fish, both in bony fish^{[9] [10]} and cartilaginous fish;^[11] because at that evolutionary level they can't be distinguished as IL-4 or IL-13, they have been named IL-4/13.

Discovery

This cytokine was co-discovered by Maureen Howard and William E. Paul^[12] as well as by Ellen Vitetta and her research group in 1982.

The nucleotide sequence for human IL-4 was isolated four years later confirming its similarity to a mouse protein called B cell stimulatory factor-1 (BCSF-1).^[13]

Animal studies

IL-4 has been found to mediate a crosstalk between the neural stem cells and neurons that undergo neurodegeneration, and initiate a regeneration cascade through phosphorylation of its intracellular effector STAT6 in an experimental Alzheimer's disease model in adult zebrafish brain.^[14]

Clinical significance

IL-4 has also been shown to drive mitogenesis, dedifferentiation, and metastasis in rhabdomyosarcoma.^[15] IL-4, along with other Th2 cytokines, is involved in the airway inflammation observed in the lungs of patients with allergic asthma.^[16]

Illnesses associated with IL-4

IL-4 plays an important role in the development of certain immune disorders, particularly allergies and some autoimmune diseases.

Allergic diseases

Allergic diseases are sets of disorders that are manifested by a disproportionate response of the immune system to the allergen and T_h2 responses. These pathologies include, for example, atopic dermatitis, asthma, or systemic anaphylaxis. Interleukin 4 mediates important pro-inflammatory functions in asthma, including induction of isotype rearrangement of IgE, expression of vascular cell adhesion molecule 1 (VCAM-1), promoting eosinophilic transmigration through endothelium, mucus secretion and T helper type 2 (T_h2) leading to cytokine release. Asthma is a complex genetic disorder that has been associated with IL-4 gene promoter polymorphism and proteins involved in IL-4 signaling.^[17]

Tumors

IL-4 has a significant effect on tumor progression. Increased IL-4 production was found in breast, prostate, lung, renal cells and other types of cancer. Overexpression of IL-4R has been found in many types of cancer. Renal cells and glioblastoma modify  - receptors per cell depending on tumor type.^[18]

IL-4 can primitively motivate tumor cells and increase their apoptosis resistance by increasing tumor growth.^[19]

Nervous system

Brain tissue tumors such as astrocytoma, glioblastoma, meningioma, and medulloblastoma overexpress receptors for various growth factors including epidermal growth factor receptor, FGFR-1 (fibroblast growth factor receptor 1), TfR (transferrin receptor), IL-13R. Most human meningiomas massively expresses IL-4 receptors, indicating its role in cancer progression. They express IL-4Rα and IL13Rα-1-1, but not the surface γc chain, suggesting that most human meningiomas express IL-4 type II.^[20]

HIV

IL-4 may also play a role in the infection and development of HIV disease. Auxiliary T cells are a key element of HIV-1 infection. Several signs of immune dysregulation such as polyclonal B cell initialization, previous cell-mediated antigen-induced response and hypergammaglobulinaemia occur in most HIV-1 infected patients and are associated with cytokines synthesized by T_h2 cells. Increased IL-4 production by T_h2 cells has been demonstrated in people infected with HIV.^[21]

See also

• STAT6

Further reading

• Zhu H, Wang Z, Yu J, Yang X, He F, Liu Z, Che F, Chen X, Ren H, Hong M, Wang J . 6 . Role and mechanisms of cytokines in the secondary brain injury after intracerebral hemorrhage . Progress in Neurobiology . 178 . 101610 . July 2019 . 30923023 . 10.1016/j.pneurobio.2019.03.003 . 85495400 .
• Apte SH, Baz A, Groves P, Kelso A, Kienzle N . Interferon-gamma and interleukin-4 reciprocally regulate CD8 expression in CD8+ T cells . Proceedings of the National Academy of Sciences of the United States of America . 105 . 45 . 17475–17480 . November 2008 . 18988742 . 2580749 . 10.1073/pnas.0809549105 . free . 2008PNAS..10517475A .
• Kay AB, Barata L, Meng Q, Durham SR, Ying S . Eosinophils and eosinophil-associated cytokines in allergic inflammation . International Archives of Allergy and Immunology . 113 . 1–3 . 196–199 . 1997 . 9130521 . 10.1159/000237545 .
• Marone G, Florio G, Petraroli A, de Paulis A . Dysregulation of the IgE/Fc epsilon RI network in HIV-1 infection . The Journal of Allergy and Clinical Immunology . 107 . 1 . 22–30 . January 2001 . 11149986 . 10.1067/mai.2001.111589 . free .
• Marone G, Florio G, Triggiani M, Petraroli A, de Paulis A . Mechanisms of IgE elevation in HIV-1 infection . Critical Reviews in Immunology . 20 . 6 . 477–496 . 2001 . 11396683 . 10.1615/critrevimmunol.v20.i6.40 .
• Maeda S, Yanagihara Y . [Inflammatory cytokines (IL-4, IL-5 and IL-13)] . Nihon Rinsho. Japanese Journal of Clinical Medicine . 59 . 10 . 1894–1899 . October 2001 . 11676128 .
• Izuhara K, Arima K, Yasunaga S . IL-4 and IL-13: their pathological roles in allergic diseases and their potential in developing new therapies . Current Drug Targets. Inflammation and Allergy . 1 . 3 . 263–269 . September 2002 . 14561191 . 10.2174/1568010023344661 .
• Copeland KF . Modulation of HIV-1 transcription by cytokines and chemokines . Mini Reviews in Medicinal Chemistry . 5 . 12 . 1093–1101 . December 2005 . 16375755 . 10.2174/138955705774933383 .
• Olver S, Apte S, Baz A, Kienzle N . The duplicitous effects of interleukin 4 on tumour immunity: how can the same cytokine improve or impair control of tumour growth? . Tissue Antigens . 69 . 4 . 293–298 . April 2007 . 17389011 . 10.1111/j.1399-0039.2007.00831.x . free .
• Sokol CL, Chu NQ, Yu S, Nish SA, Laufer TM, Medzhitov R . Basophils function as antigen-presenting cells for an allergen-induced T helper type 2 response . Nature Immunology . 10 . 7 . 713–720 . July 2009 . 19465907 . 3252751 . 10.1038/ni.1738 .
• Sokol CL, Chu NQ, Yu S, Nish SA, Laufer TM, Medzhitov R . Basophils function as antigen-presenting cells for an allergen-induced T helper type 2 response . Nature Immunology . 10 . 7 . 713–720 . July 2009 . 19465907 . 3252751 . 10.1038/ni.1738 .

External links

• • Interleukin-4 from Gentaur
• Recombinant Human Interleukin-4 from Cornell University
• Interleukin-4 from Allergy Glossary at Health On the Net Foundation

Notes and References

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2. Hershey GK, Friedrich MF, Esswein LA, Thomas ML, Chatila TA . The association of atopy with a gain-of-function mutation in the alpha subunit of the interleukin-4 receptor . The New England Journal of Medicine . 337 . 24 . 1720–1725 . December 1997 . 9392697 . 10.1056/NEJM199712113372403 . free .
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4. Maes T, Joos GF, Brusselle GG . Targeting interleukin-4 in asthma: lost in translation? . American Journal of Respiratory Cell and Molecular Biology . 47 . 3 . 261–270 . September 2012 . 22538865 . 10.1165/rcmb.2012-0080TR .
5. Chatila TA . Interleukin-4 receptor signaling pathways in asthma pathogenesis . Trends in Molecular Medicine . 10 . 10 . 493–499 . October 2004 . 15464449 . 10.1016/j.molmed.2004.08.004 .
6. Carr C, Aykent S, Kimack NM, Levine AD . Disulfide assignments in recombinant mouse and human interleukin 4 . Biochemistry . 30 . 6 . 1515–1523 . February 1991 . 1993171 . 10.1021/bi00220a011 .
7. Walter MR, Cook WJ, Zhao BG, Cameron RP, Ealick SE, Walter RL, Reichert P, Nagabhushan TL, Trotta PP, Bugg CE . 6 . Crystal structure of recombinant human interleukin-4 . The Journal of Biological Chemistry . 267 . 28 . 20371–20376 . October 1992 . 1400355 . 10.2210/pdb2int/pdb . 2310949 .
8. Zhu J . T helper 2 (Th2) cell differentiation, type 2 innate lymphoid cell (ILC2) development and regulation of interleukin-4 (IL-4) and IL-13 production . Cytokine . 75 . 1 . 14–24 . September 2015 . 26044597 . 4532589 . 10.1016/j.cyto.2015.05.010 .
9. Li JH, Shao JZ, Xiang LX, Wen Y . Cloning, characterization and expression analysis of pufferfish interleukin-4 cDNA: the first evidence of Th2-type cytokine in fish . Molecular Immunology . 44 . 8 . 2078–2086 . March 2007 . 17084456 . 10.1016/j.molimm.2006.09.010 .
10. Ohtani M, Hayashi N, Hashimoto K, Nakanishi T, Dijkstra JM . Comprehensive clarification of two paralogous interleukin 4/13 loci in teleost fish . Immunogenetics . 60 . 7 . 383–397 . July 2008 . 18560827 . 10.1007/s00251-008-0299-x . 24675205 .
11. Dijkstra JM . TH2 and Treg candidate genes in elephant shark . Nature . 511 . 7508 . E7–E9 . July 2014 . 25008534 . 10.1038/nature13446 . 4447611 .
12. Howard M, Paul WE . Interleukins for B lymphocytes . Lymphokine Research . 1 . 1 . 1–4 . 1982 . 6985399 .
13. Yokota T, Otsuka T, Mosmann T, Banchereau J, DeFrance T, Blanchard D, De Vries JE, Lee F, Arai K . 6 . Isolation and characterization of a human interleukin cDNA clone, homologous to mouse B-cell stimulatory factor 1, that expresses B-cell- and T-cell-stimulating activities . Proceedings of the National Academy of Sciences of the United States of America . 83 . 16 . 5894–5898 . August 1986 . 3016727 . 386403 . 10.1073/pnas.83.16.5894 . free . 1986PNAS...83.5894Y .
14. Bhattarai P, Thomas AK, Cosacak MI, Papadimitriou C, Mashkaryan V, Froc C, Reinhardt S, Kurth T, Dahl A, Zhang Y, Kizil C . 6 . IL4/STAT6 Signaling Activates Neural Stem Cell Proliferation and Neurogenesis upon Amyloid-β42 Aggregation in Adult Zebrafish Brain . Cell Reports . 17 . 4 . 941–948 . October 2016 . 27760324 . 10.1016/j.celrep.2016.09.075 . free .
15. Hosoyama T, Aslam MI, Abraham J, Prajapati SI, Nishijo K, Michalek JE, Zarzabal LA, Nelon LD, Guttridge DC, Rubin BP, Keller C . 6 . IL-4R drives dedifferentiation, mitogenesis, and metastasis in rhabdomyosarcoma . Clinical Cancer Research . 17 . 9 . 2757–2766 . May 2011 . 21536546 . 3087179 . 10.1158/1078-0432.CCR-10-3445 .
16. Gour N, Wills-Karp M . IL-4 and IL-13 signaling in allergic airway disease . Cytokine . 75 . 1 . 68–78 . September 2015 . 26070934 . 4532591 . 10.1016/j.cyto.2015.05.014 .
17. Steinke JW, Borish L . Th2 cytokines and asthma. Interleukin-4: its role in the pathogenesis of asthma, and targeting it for asthma treatment with interleukin-4 receptor antagonists . Respiratory Research . 2 . 2 . 66–70 . 19 February 2001 . 11686867 . 59570 . 10.1186/rr40 . free .
18. Ul-Haq Z, Naz S, Mesaik MA . Interleukin-4 receptor signaling and its binding mechanism: A therapeutic insight from inhibitors tool box . Cytokine & Growth Factor Reviews . 32 . 3–15 . December 2016 . 27165851 . 10.1016/j.cytogfr.2016.04.002 .
19. Li Z, Jiang J, Wang Z, Zhang J, Xiao M, Wang C, Lu Y, Qin Z . 6 . Endogenous interleukin-4 promotes tumor development by increasing tumor cell resistance to apoptosis . Cancer Research . 68 . 21 . 8687–8694 . November 2008 . 18974110 . 10.1158/0008-5472.CAN-08-0449 . free .
20. Puri S, Joshi BH, Sarkar C, Mahapatra AK, Hussain E, Sinha S . Expression and structure of interleukin 4 receptors in primary meningeal tumors . Cancer . 103 . 10 . 2132–2142 . May 2005 . 15830341 . 10.1002/cncr.21008 . 42324572 . free .
21. Meyaard L, Hovenkamp E, Keet IP, Hooibrink B, de Jong IH, Otto SA, Miedema F . Single cell analysis of IL-4 and IFN-gamma production by T cells from HIV-infected individuals: decreased IFN-gamma in the presence of preserved IL-4 production . Journal of Immunology . 157 . 6 . 2712–2718 . September 1996 . 10.4049/jimmunol.157.6.2712 . 8805678 . 39431866 .