View source for Interleukin 4

{{Short description|Mammalian protein found in Mus musculus}}
{{Infobox_gene}}
{{Infobox protein family
| Symbol = IL4
| Name = Interleukin 4
| image = PDB 1itm EBI.jpg
| width = 
| caption = analysis of the solution structure of human interleukin 4 determined by heteronuclear three-dimensional nuclear magnetic resonance techniques
| Pfam = PF00727
| Pfam_clan = CL0053 
| InterPro = IPR002354
| SMART = 
| PROSITE = PDOC00655
| MEROPS = 
| SCOP = 2int
| TCDB = 
| OPM family = 
| OPM protein = 
| CAZy = 
| CDD = 
}}
The '''interleukin 4''' ('''IL4''', '''IL-4''') is a [[cytokine]] that induces differentiation of naive helper T cells ([[Naive T cell|T<sub>h</sub>0&nbsp;cells]]) to [[T helper cell|T<sub>h</sub>2&nbsp;cells]]. Upon activation by IL-4, T<sub>h</sub>2&nbsp;cells subsequently produce additional IL-4 in a [[positive feedback]] loop. IL-4 is produced primarily by mast cells, T<sub>h</sub>2&nbsp;cells, eosinophils and basophils.<ref>{{cite journal | vauthors = Gadani SP, Cronk JC, Norris GT, Kipnis J | title = IL-4 in the brain: a cytokine to remember | journal = Journal of Immunology | volume = 189 | issue = 9 | pages = 4213–4219 | date = November 2012 | pmid = 23087426 | pmc = 3481177 | doi = 10.4049/jimmunol.1202246 }}</ref> It is closely related and has functions similar to [[Interleukin 13|IL-13]].

== Function ==

Interleukin 4 has many biological roles, including the stimulation of activated [[B cell]] and [[T cell]] [[cell growth|proliferation]], and the differentiation of B&nbsp;cells into [[plasma cell]]s. It is a key regulator in [[humoral immunity|humoral]] and [[adaptive immunity]].   IL-4 induces B&nbsp;cell [[class switching]] to [[IgE]], and up-regulates [[MHC class II]] production.  IL-4 decreases the production of [[T helper cell|T<sub>h</sub>1&nbsp;cells]], macrophages, [[Interferon gamma|IFNγ]], and [[dendritic cell]]s [[Interleukin 12|IL-12]].

Overproduction of IL-4 is associated with [[allergies]].<ref name="pmid9392697">{{cite journal | vauthors = Hershey GK, Friedrich MF, Esswein LA, Thomas ML, Chatila TA | title = The association of atopy with a gain-of-function mutation in the alpha subunit of the interleukin-4 receptor | journal = The New England Journal of Medicine | volume = 337 | issue = 24 | pages = 1720–1725 | date = December 1997 | pmid = 9392697 | doi = 10.1056/NEJM199712113372403 | doi-access = free }}
*{{lay source |template=cite press release|url = https://web.archive.org/web/20110607151336/http://www.eurekalert.org/pub_releases/1997-12/WUSo-SISG-101297.php|title = Scientists Identify Strong Genetic Link To Allergies|date = December 10, 1997 |website = EurekAlert.org }}</ref>

=== Inflammation and wound repair ===

[[Macrophage#Fixed macrophages|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 [[Interleukin 10|IL-10]] and [[Transforming growth factor beta|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]].<ref name="isbn1-4160-3121-9">{{cite book | author = Jon Aster | author2 = Vinay Kumar | author3 = Abul K. Abbas | author4 = Nelson Fausto | title = Robbins & Cotran Pathologic Basis of Disease | edition = 8th | publisher = Saunders | location = Philadelphia | year = 2009 | page = 54 | isbn = 978-1-4160-3121-5 }}</ref>

== Receptor ==

The receptor for interleukin-4 is known as the [[Interleukin-4 receptor|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.<ref name="pmid22538865">{{cite journal | vauthors = Maes T, Joos GF, Brusselle GG | title = Targeting interleukin-4 in asthma: lost in translation? | journal = American Journal of Respiratory Cell and Molecular Biology | volume = 47 | issue = 3 | pages = 261–270 | date = September 2012 | pmid = 22538865 | doi = 10.1165/rcmb.2012-0080TR | url = https://biblio.ugent.be/publication/2964188/file/6776466 | url-access = subscription }}</ref><ref name="pmid15464449">{{cite journal | vauthors = Chatila TA | title = Interleukin-4 receptor signaling pathways in asthma pathogenesis | journal = Trends in Molecular Medicine | volume = 10 | issue = 10 | pages = 493–499 | date = October 2004 | pmid = 15464449 | doi = 10.1016/j.molmed.2004.08.004 }}</ref>

== Structure ==

IL-4 has a compact, globular [[protein folding|fold]] (similar to other [[cytokines]]), stabilised by 3 [[disulphide bonds]].<ref name="pmid1993171">{{cite journal | vauthors = Carr C, Aykent S, Kimack NM, Levine AD | title = Disulfide assignments in recombinant mouse and human interleukin 4 | journal = Biochemistry | volume = 30 | issue = 6 | pages = 1515–1523 | date = February 1991 | pmid = 1993171 | doi = 10.1021/bi00220a011 }}</ref> One half of the structure is dominated by a 4 [[alpha-helix]] bundle with a left-handed twist.<ref name="pmid1400355">{{cite journal | vauthors = Walter MR, Cook WJ, Zhao BG, Cameron RP, Ealick SE, Walter RL, Reichert P, Nagabhushan TL, Trotta PP, Bugg CE | display-authors = 6 | title = Crystal structure of recombinant human interleukin-4 | journal = The Journal of Biological Chemistry | volume = 267 | issue = 28 | pages = 20371–20376 | date = October 1992 | pmid = 1400355 | doi = 10.2210/pdb2int/pdb | s2cid = 2310949 }}</ref> The helices are [[Antiparallel (biochemistry)|anti-parallel]], with 2 overhand connections, which fall into a 2-stranded anti-parallel [[beta-sheet]].<ref name="pmid1400355" />

== Evolution ==
IL-4 is closely related to [[Interleukin 13|IL-13]], and both stimulate [[Type 2 inflammation|type 2 immunity]].<ref>{{cite journal | vauthors = Zhu J | title = T helper 2 (Th2) cell differentiation, type 2 innate lymphoid cell (ILC2) development and regulation of interleukin-4 (IL-4) and IL-13 production | journal = Cytokine | volume = 75 | issue = 1 | pages = 14–24 | date = September 2015 | pmid = 26044597 | pmc = 4532589 | doi = 10.1016/j.cyto.2015.05.010 }}</ref> Genes of this family have also been found in fish, both in bony fish<ref>{{cite journal | vauthors = Li JH, Shao JZ, Xiang LX, Wen Y | title = Cloning, characterization and expression analysis of pufferfish interleukin-4 cDNA: the first evidence of Th2-type cytokine in fish | journal = Molecular Immunology | volume = 44 | issue = 8 | pages = 2078–2086 | date = March 2007 | pmid = 17084456 | doi = 10.1016/j.molimm.2006.09.010 }}</ref><ref name=":0">{{cite journal | vauthors = Ohtani M, Hayashi N, Hashimoto K, Nakanishi T, Dijkstra JM | title = Comprehensive clarification of two paralogous interleukin 4/13 loci in teleost fish | journal = Immunogenetics | volume = 60 | issue = 7 | pages = 383–397 | date = July 2008 | pmid = 18560827 | doi = 10.1007/s00251-008-0299-x | s2cid = 24675205 }}</ref> and cartilaginous fish;<ref>{{cite journal | vauthors = Dijkstra JM | title = TH2 and Treg candidate genes in elephant shark | journal = Nature | volume = 511 | issue = 7508 | pages = E7–E9 | date = July 2014 | pmid = 25008534 | doi = 10.1038/nature13446 | s2cid = 4447611 }}</ref> because at that evolutionary level they can't be distinguished as IL-4 or IL-13, they have been named IL-4/13.<ref name=":0" />

== Discovery ==
This cytokine was co-discovered by Maureen Howard and [[William E. Paul]]<ref>{{cite journal | vauthors = Howard M, Paul WE | title = Interleukins for B lymphocytes | journal = Lymphokine Research | volume = 1 | issue = 1 | pages = 1–4 | year = 1982 | pmid = 6985399 }}</ref> 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&nbsp;cell stimulatory factor-1 (BCSF-1).<ref>{{cite journal | vauthors = Yokota T, Otsuka T, Mosmann T, Banchereau J, DeFrance T, Blanchard D, De Vries JE, Lee F, Arai K | display-authors = 6 | title = 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 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 83 | issue = 16 | pages = 5894–5898 | date = August 1986 | pmid = 3016727 | pmc = 386403 | doi = 10.1073/pnas.83.16.5894 | doi-access = free | bibcode = 1986PNAS...83.5894Y }}</ref>

== 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.<ref>{{cite journal | vauthors = Bhattarai P, Thomas AK, Cosacak MI, Papadimitriou C, Mashkaryan V, Froc C, Reinhardt S, Kurth T, Dahl A, Zhang Y, Kizil C | display-authors = 6 | title = IL4/STAT6 Signaling Activates Neural Stem Cell Proliferation and Neurogenesis upon Amyloid-β42 Aggregation in Adult Zebrafish Brain | journal = Cell Reports | volume = 17 | issue = 4 | pages = 941–948 | date = October 2016 | pmid = 27760324 | doi = 10.1016/j.celrep.2016.09.075 | doi-access = free }}</ref>

== Clinical significance ==

IL-4 has also been shown to drive [[mitogenesis]], [[cellular differentiation|dedifferentiation]], and [[metastasis]] in [[rhabdomyosarcoma]].<ref name="pmid21536546">{{cite journal | vauthors = Hosoyama T, Aslam MI, Abraham J, Prajapati SI, Nishijo K, Michalek JE, Zarzabal LA, Nelon LD, Guttridge DC, Rubin BP, Keller C | display-authors = 6 | title = IL-4R drives dedifferentiation, mitogenesis, and metastasis in rhabdomyosarcoma | journal = Clinical Cancer Research | volume = 17 | issue = 9 | pages = 2757–2766 | date = May 2011 | pmid = 21536546 | pmc = 3087179 | doi = 10.1158/1078-0432.CCR-10-3445 }}</ref> IL-4, along with other Th2 cytokines, is involved in the airway inflammation observed in the lungs of patients with allergic [[asthma]].<ref name="pmid26070934">{{cite journal | vauthors = Gour N, Wills-Karp M | title = IL-4 and IL-13 signaling in allergic airway disease | journal = Cytokine | volume = 75 | issue = 1 | pages = 68–78 | date = September 2015 | pmid = 26070934 | pmc = 4532591 | doi = 10.1016/j.cyto.2015.05.014 }}</ref>

== 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<sub>h</sub>2 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<sub>h</sub>2) 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.<ref>{{cite journal | vauthors = Steinke JW, Borish L | title = Th2 cytokines and asthma. Interleukin-4: its role in the pathogenesis of asthma, and targeting it for asthma treatment with interleukin-4 receptor antagonists | journal = Respiratory Research | volume = 2 | issue = 2 | pages = 66–70 | date = 19 February 2001 | pmid = 11686867 | pmc = 59570 | doi = 10.1186/rr40 | doi-access = free }}</ref>

===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 {{val|10000}}&ndash;{{val|13000}} receptors per cell depending on tumor type.<ref>{{cite journal | vauthors = Ul-Haq Z, Naz S, Mesaik MA | title = Interleukin-4 receptor signaling and its binding mechanism: A therapeutic insight from inhibitors tool box | journal = Cytokine & Growth Factor Reviews | volume = 32 | pages = 3–15 | date = December 2016 | pmid = 27165851 | doi = 10.1016/j.cytogfr.2016.04.002 }}</ref>

IL-4 can primitively motivate tumor cells and increase their apoptosis resistance by increasing tumor growth.<ref>{{cite journal | vauthors = Li Z, Jiang J, Wang Z, Zhang J, Xiao M, Wang C, Lu Y, Qin Z | display-authors = 6 | title = Endogenous interleukin-4 promotes tumor development by increasing tumor cell resistance to apoptosis | journal = Cancer Research | volume = 68 | issue = 21 | pages = 8687–8694 | date = November 2008 | pmid = 18974110 | doi = 10.1158/0008-5472.CAN-08-0449 | doi-access = free }}</ref>

===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.<ref>{{cite journal | vauthors = Puri S, Joshi BH, Sarkar C, Mahapatra AK, Hussain E, Sinha S | title = Expression and structure of interleukin 4 receptors in primary meningeal tumors | journal = Cancer | volume = 103 | issue = 10 | pages = 2132–2142 | date = May 2005 | pmid = 15830341 | doi = 10.1002/cncr.21008 | s2cid = 42324572 | doi-access = free }}</ref>

===HIV===
IL-4 may also play a role in the infection and development of [[HIV/AIDS|HIV disease]]. Auxiliary T&nbsp;cells are a key element of HIV-1 infection. Several signs of immune dysregulation such as polyclonal B&nbsp;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<sub>h</sub>2&nbsp;cells. Increased IL-4 production by T<sub>h</sub>2&nbsp;cells has been demonstrated in people infected with HIV.<ref>{{cite journal | vauthors = Meyaard L, Hovenkamp E, Keet IP, Hooibrink B, de Jong IH, Otto SA, Miedema F | title = 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 = Journal of Immunology | volume = 157 | issue = 6 | pages = 2712–2718 | date = September 1996 | doi = 10.4049/jimmunol.157.6.2712 | pmid = 8805678 | s2cid = 39431866 }}</ref>

== See also ==
* [[STAT6]]
* [[IL-4-inhibitor-1]]

== References ==
* {{InterPro content|IPR002354}}
{{Reflist}}

== Further reading ==
{{Refbegin|30em}}
* {{cite journal | vauthors = Zhu H, Wang Z, Yu J, Yang X, He F, Liu Z, Che F, Chen X, Ren H, Hong M, Wang J | display-authors = 6 | title = Role and mechanisms of cytokines in the secondary brain injury after intracerebral hemorrhage | journal = Progress in Neurobiology | volume = 178 | pages = 101610 | date = July 2019 | pmid = 30923023 | doi = 10.1016/j.pneurobio.2019.03.003 | s2cid = 85495400 }}
* {{cite journal | vauthors = Apte SH, Baz A, Groves P, Kelso A, Kienzle N | title = Interferon-gamma and interleukin-4 reciprocally regulate CD8 expression in CD8+ T cells | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 45 | pages = 17475–17480 | date = November 2008 | pmid = 18988742 | pmc = 2580749 | doi = 10.1073/pnas.0809549105 | doi-access = free | bibcode = 2008PNAS..10517475A }}
* {{cite journal | vauthors = Kay AB, Barata L, Meng Q, Durham SR, Ying S | title = Eosinophils and eosinophil-associated cytokines in allergic inflammation | journal = International Archives of Allergy and Immunology | volume = 113 | issue = 1–3 | pages = 196–199 | year = 1997 | pmid = 9130521 | doi = 10.1159/000237545 }}
* {{cite journal | vauthors = Marone G, Florio G, Petraroli A, de Paulis A | title = Dysregulation of the IgE/Fc epsilon RI network in HIV-1 infection | journal = The Journal of Allergy and Clinical Immunology | volume = 107 | issue = 1 | pages = 22–30 | date = January 2001 | pmid = 11149986 | doi = 10.1067/mai.2001.111589 | doi-access = free }}
* {{cite journal | vauthors = Marone G, Florio G, Triggiani M, Petraroli A, de Paulis A | title = Mechanisms of IgE elevation in HIV-1 infection | journal = Critical Reviews in Immunology | volume = 20 | issue = 6 | pages = 477–496 | year = 2001 | pmid = 11396683 | doi = 10.1615/critrevimmunol.v20.i6.40 }}
* {{cite journal | vauthors = Maeda S, Yanagihara Y | title = [Inflammatory cytokines (IL-4, IL-5 and IL-13)] | journal = Nihon Rinsho. Japanese Journal of Clinical Medicine | volume = 59 | issue = 10 | pages = 1894–1899 | date = October 2001 | pmid = 11676128 }}
* {{cite journal | vauthors = Izuhara K, Arima K, Yasunaga S | title = IL-4 and IL-13: their pathological roles in allergic diseases and their potential in developing new therapies | journal = Current Drug Targets. Inflammation and Allergy | volume = 1 | issue = 3 | pages = 263–269 | date = September 2002 | pmid = 14561191 | doi = 10.2174/1568010023344661 }}
* {{cite journal | vauthors = Copeland KF | title = Modulation of HIV-1 transcription by cytokines and chemokines | journal = Mini Reviews in Medicinal Chemistry | volume = 5 | issue = 12 | pages = 1093–1101 | date = December 2005 | pmid = 16375755 | doi = 10.2174/138955705774933383 }}
* {{cite journal | vauthors = Olver S, Apte S, Baz A, Kienzle N | title = The duplicitous effects of interleukin 4 on tumour immunity: how can the same cytokine improve or impair control of tumour growth? | journal = Tissue Antigens | volume = 69 | issue = 4 | pages = 293–298 | date = April 2007 | pmid = 17389011 | doi = 10.1111/j.1399-0039.2007.00831.x | doi-access = free }}
* {{cite journal | vauthors = Sokol CL, Chu NQ, Yu S, Nish SA, Laufer TM, Medzhitov R | title = Basophils function as antigen-presenting cells for an allergen-induced T helper type 2 response | journal = Nature Immunology | volume = 10 | issue = 7 | pages = 713–720 | date = July 2009 | pmid = 19465907 | pmc = 3252751 | doi = 10.1038/ni.1738 }}
* {{cite journal | vauthors = Sokol CL, Chu NQ, Yu S, Nish SA, Laufer TM, Medzhitov R | title = Basophils function as antigen-presenting cells for an allergen-induced T helper type 2 response | journal = Nature Immunology | volume = 10 | issue = 7 | pages = 713–720 | date = July 2009 | pmid = 19465907 | pmc = 3252751 | doi = 10.1038/ni.1738 }}
{{Refend}}

== External links ==
* {{MeshName|Interleukin-4}}
* [https://gentaur.co.uk/shop/interleukin-4-il4-recombinant-protein-cloud-clone-338-cat-4-rpa077mu01/ Interleukin-4] from [[Gentaur]]
* [http://arginine.chem.cornell.edu/Structures/IL4.html Recombinant Human Interleukin-4] from [[Cornell University]]
* [http://www.hon.ch/Library/Theme/Allergy/Glossary/il4.html Interleukin-4 from Allergy Glossary] at [[Health On the Net Foundation]]
* {{PDBe-KB2|P05112|Interleukin-4}}

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[[Category:Protein domains]]
[[Category:Interleukins]]