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<!-- The PBB_Controls template provides controls for Protein Box Bot, please see Template:PBB_Controls for details. -->
{{Infobox_gene}}
{{PBB_Controls
{{Infobox protein family
| update_page = yes
| Symbol = IL4
| require_manual_inspection = no
| Name = Interleukin 4
| update_protein_box = yes
| image = PDB 1itm EBI.jpg
| update_summary = no
| width =
| update_citations = yes
| 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 ([[Th0 cell]]s) to [[Th2 cell]]s. Upon activation by IL-4, [[Th2 cell]]s subsequently produce additional IL-4 in a [[positive feedback]] loop. The cell that initially produces IL-4, thus inducing Th2 differentiation, has not been identified, but recent studies suggest that [[basophils]] may be the effector cell.<ref>{{cite journal |author=Sokol, C.L., Barton, G.M., Farr, A.G. & Medzhitov, R. |title=A mechanism for the initiation of allergen-induced T helper type 2 responses |journal=Nat Immunol |volume=9 |pages=310–318 |year=2008 |pmid=18300366 |doi=10.1038/ni1558 |issue=3|pmc=3888112 }}</ref> It is closely related and has functions similar to [[Interleukin 13]].


<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot. See Template:PBB_Controls to Stop updates. -->
== Function ==
{{GNF_Protein_box
 
| image = IL4_Crystal_Structure_recombinant.png
Interleukin 4 has many biological roles, including the stimulation of activated [[B-cell]] and [[T-cell]] [[cell growth|proliferation]], and the differentiation of B cells into [[plasma cells]]. It is a key regulator in [[humoral immunity|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 [[Th1 cell]]s, macrophages, [[IFN-gamma]], and [[dendritic cell]] [[Interleukin 12|IL-12]].
| image_source = Crystal structure of human IL-4 (2INT)
 
| PDB = {{PDB2|1bbn}}, {{PDB2|1bcn}}, {{PDB2|1cyl}}, {{PDB2|1hij}}, {{PDB2|1hik}}, {{PDB2|1hzi}}, {{PDB2|1iar}}, {{PDB2|1iti}}, {{PDB2|1itl}}, {{PDB2|1itm}}, {{PDB2|1rcb}}, {{PDB2|2b8u}}, {{PDB2|2b8x}}, {{PDB2|2b8y}}, {{PDB2|2b8z}}, {{PDB2|2b90}}, {{PDB2|2b91}}, {{PDB2|2cyk}}, {{PDB2|2d48}}, {{PDB2|2int}}
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 = N. Engl. J. Med. | volume = 337 | issue = 24 | pages = 1720–5 |date=December 1997 | pmid = 9392697 | doi = 10.1056/NEJM199712113372403 | laysummary = http://www.eurekalert.org/pub_releases/1997-12/WUSo-SISG-101297.php | laysource = eurekalert.org }}</ref>
| Name = Interleukin 4
 
| HGNCid = 6014
=== Inflammation and wound repair ===
| Symbol = IL4
 
| AltSymbols =; BSF1; IL-4; MGC79402
[[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, Vinay Kumar, Abul K. Abbas; Nelson Fausto | title = Robbins & Cotran Pathologic Basis of Disease | edition = 8th | language = | publisher = Saunders | location = Philadelphia | year = 2009 | origyear = | page = 54 | quote = | isbn = 1-4160-3121-9 | oclc = | doi = | url = | accessdate = }}</ref>
| OMIM = 147780
 
| ECnumber =
== Receptor ==
| Homologene = 491
 
| MGIid = 96556
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 = Am. J. Respir. Cell Mol. Biol. | volume = 47 | issue = 3 | pages = 261–70 |date=September 2012 | pmid = 22538865 | doi = 10.1165/rcmb.2012-0080TR }}</ref><ref name="pmid15464449">{{cite journal | author = Chatila TA | title = Interleukin-4 receptor signaling pathways in asthma pathogenesis | journal = Trends Mol Med | volume = 10 | issue = 10 | pages = 493–9 |date=October 2004 | pmid = 15464449 | doi = 10.1016/j.molmed.2004.08.004 }}</ref>
| GeneAtlas_image1 = PBB_GE_IL4_207539_s_at_tn.png
 
| GeneAtlas_image2 = PBB_GE_IL4_207538_at_tn.png
== Structure ==
| Function = {{GNF_GO|id=GO:0005136 |text = interleukin-4 receptor binding}} {{GNF_GO|id=GO:0005515 |text = protein binding}}
 
| Component = {{GNF_GO|id=GO:0005576 |text = extracellular region}} {{GNF_GO|id=GO:0005615 |text = extracellular space}}  
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 = 1515–23 |date=February 1991 | pmid = 1993171 | doi = 10.1021/bi00220a011| url = }}</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 | title = Crystal structure of recombinant human interleukin-4 | journal = J. Biol. Chem. | volume = 267 | issue = 28 | pages = 20371–6 |date=October 1992 | pmid = 1400355 | doi = | url = }}</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" />
| Process = {{GNF_GO|id=GO:0006935 |text = chemotaxis}} {{GNF_GO|id=GO:0006968 |text = cellular defense response}} {{GNF_GO|id=GO:0008203 |text = cholesterol metabolic process}} {{GNF_GO|id=GO:0030183 |text = B cell differentiation}} {{GNF_GO|id=GO:0030890 |text = positive regulation of B cell proliferation}} {{GNF_GO|id=GO:0042092 |text = T-helper 2 type immune response}} {{GNF_GO|id=GO:0042104 |text = positive regulation of activated T cell proliferation}} {{GNF_GO|id=GO:0042325 |text = regulation of phosphorylation}} {{GNF_GO|id=GO:0042523 |text = positive regulation of tyrosine phosphorylation of Stat5 protein}} {{GNF_GO|id=GO:0043066 |text = negative regulation of apoptosis}} {{GNF_GO|id=GO:0045189 |text = connective tissue growth factor biosynthetic process}} {{GNF_GO|id=GO:0045191 |text = regulation of isotype switching}} {{GNF_GO|id=GO:0045348 |text = positive regulation of MHC class II biosynthetic process}} {{GNF_GO|id=GO:0045671 |text = negative regulation of osteoclast differentiation}} {{GNF_GO|id=GO:0045944 |text = positive regulation of transcription from RNA polymerase II promoter}} {{GNF_GO|id=GO:0048295 |text = positive regulation of isotype switching to IgE isotypes}} {{GNF_GO|id=GO:0048304 |text = positive regulation of isotype switching to IgG isotypes}} {{GNF_GO|id=GO:0050776 |text = regulation of immune response}}  
 
| Orthologs = {{GNF_Ortholog_box
== Discovery ==
    | Hs_EntrezGene = 3565
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 Res. |volume=1 |issue=1 |pages=1–4 |year=1982 |pmid=6985399 |doi=}}</ref> as well as by [[Ellen Vitetta]] and her research group in 1982.
    | Hs_Ensembl = ENSG00000113520
 
    | Hs_RefseqProtein = NP_000580
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).<ref>{{cite journal  |vauthors=Yokota T, etal |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=Proc. Natl. Acad. Sci. U.S.A. |volume=83 |issue=16 |pages=5894–8 |year=1986 |pmid=3016727 |doi=10.1073/pnas.83.16.5894 |pmc=386403}}</ref>
    | Hs_RefseqmRNA = NM_000589
 
    | Hs_GenLoc_db =
== Animal studies ==
    | Hs_GenLoc_chr = 5
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 |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= 941–8 |year= 2016 |pmid= 27760324 |doi= 10.1016/j.celrep.2016.09.075 }}</ref>
    | Hs_GenLoc_start = 132037272
 
    | Hs_GenLoc_end = 132046267
== Clinical significance ==
    | Hs_Uniprot = P05112
 
    | Mm_EntrezGene = 16189
IL-4 also has 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 | title = IL-4R Drives Dedifferentiation, Mitogenesis, and Metastasis in Rhabdomyosarcoma | journal = Clin Cancer Res | volume = 17 | issue = 9 | pages = 2757–2766 |date=May 2011 | pmid = 21536546 | doi = 10.1158/1078-0432.CCR-10-3445 | pmc = 3087179 }}</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 | year = 2015 | pmid = 26070934 | pmc = 4532591 | doi = 10.1016/j.cyto.2015.05.014 }}</ref>
    | Mm_Ensembl = ENSMUSG00000000869
 
    | Mm_RefseqmRNA = NM_021283
== Illnesses associated with IL-4 ==
    | Mm_RefseqProtein = NP_067258
    | Mm_GenLoc_db =
    | Mm_GenLoc_chr = 11
    | Mm_GenLoc_start = 53455891
    | Mm_GenLoc_end = 53462067
    | Mm_Uniprot = Q5SV00
  }}
}}
{{CMG}}


==Overview==
IL-4 plays an important role in the development of certain immune disorders, particularly allergies and some autoimmune diseases.
'''Interleukin-4''', abbreviated '''IL-4''', is a [[cytokine]] that induces differentiation of naive helper T cells ([[Th0 cell]]s) to [[Th2 cell]]s. Upon activation by IL-4, Th2 cells subsequently produce additional IL-4. The cell that initially produces IL-4, thus inducing Th0 differentiation, has not been identified.


==Functions==
===Allergic diseases===
It has many biological roles, including the stimulation of activated [[B-cell]] and [[T-cell]] [[proliferation]], and the differentiation of [[CD4]]+ [[T-cells]] into [[Th2 cell]]s.  
Allergic diseases are sets of disorders that are manifested by a disproportionate response of the immune system to the allergen and Th2 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 VCAM-1 molecules (vascular cell adhesion molecule 1), promoting eosinophilic transmigration through endothelium, mucus secretion and T helper type 2 (Th2) 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 web|last1=Steinke|first1=John W.|last2=Borish|first2=Larry|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|url=https://respiratory-research.biomedcentral.com/articles/10.1186/rr40|website=Respiratory Research|pages=66|doi=10.1186/rr40|date=19 February 2001}}</ref>


It is a key regulator in [[humoral immunity|humoral]] and [[adaptive immunity]].
===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. Many overexpression of IL-4R has been found in many types of cancer. Renal cells and glioblastoma modify 10,000-13,000 receptors per cell depending on tumor type.<ref>{{cite web|last1=Ul-Haq|first1=Zaheer|last2=Naz|first2=Sehrish|last3=Mesaik|first3=M. Ahmed|title=Interleukin-4 receptor signaling and its binding mechanism: A therapeutic insight from inhibitors tool box|url=https://doi.org/10.1016/j.cytogfr.2016.04.002|website=Cytokine & Growth Factor Reviews|pages=3–15|doi=10.1016/j.cytogfr.2016.04.002}}</ref>


IL-4 induces [[B-cell]] [[class switching]] to [[IgE]], and up-regulates [[MHC class II]] production.
IL-4 can primitively motivate tumor cells and increase their apoptosis resistance by increasing tumor growth.<ref>{{cite journal|last1=Li|first1=Z.|last2=Jiang|first2=J.|last3=Wang|first3=Z.|last4=Zhang|first4=J.|last5=Xiao|first5=M.|last6=Wang|first6=C.|last7=Lu|first7=Y.|last8=Qin|first8=Z.|title=Endogenous Interleukin-4 Promotes Tumor Development by Increasing Tumor Cell Resistance to Apoptosis|journal=Cancer Research|date=1 November 2008|volume=68|issue=21|pages=8687–8694|doi=10.1158/0008-5472.CAN-08-0449}}</ref>


==History==
===Nervous system===
This cytokine was co-discovered by Maureen Howard and William Paul<ref>{{cite journal |author=Howard M, Paul WE |title=Interleukins for B lymphocytes |journal=Lymphokine Res. |volume=1 |issue=1 |pages=1-4 |year=1982 |pmid=6985399 |doi=}}</ref> and by Dr. [[Ellen Vitetta]] and her research group in [[1982]]. 
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 angiotensin 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|last1=Puri|first1=Sachin|last2=Joshi|first2=Bharat H.|last3=Sarkar|first3=Chitra|last4=Mahapatra|first4=Ashok Kumar|last5=Hussain|first5=Ejaz|last6=Sinha|first6=Subrata|title=Expression and structure of interleukin 4 receptors in primary meningeal tumors|journal=Cancer|date=15 May 2005|volume=103|issue=10|pages=2132–2142|doi=10.1002/cncr.21008}}</ref>


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).<ref>{{cite journal |author=Yokota T et al. |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=Proc. Natl. Acad. Sci. U.S.A. |volume=83 |issue=16 |pages=5894-8 |year=1986 |pmid=3016727}}</ref>
===HIV===
IL-4 may also play a role in the infection and development of [[HIV/AIDS|HIV disease]]. Auxiliary T-lymphocytes 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 Th2 cells. Increased IL-4 production by Th2 cells has been demonstrated in people infected with HIV.<ref>{{cite journal|last1=Meyaard|first1=L|last2=Hovenkamp|first2=E|last3=Keet|first3=IP|last4=Hooibrink|first4=B|last5=de Jong|first5=IH|last6=Otto|first6=SA|last7=Miedema|first7=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|date=15 September 1996|volume=157|issue=6|pages=2712–8|pmid=8805678}}</ref>


==Related Chapters==
==See also==
* [[STAT6]]
* [[STAT6]]


==References==
== References ==
{{reflist|2}}
* {{InterPro content|IPR002354}}
{{reflist|30em}}


==Further reading==
== Further reading ==
{{refbegin | 2}}
{{refbegin | 2}}
{{PBB_Further_reading
*{{cite journal  |vauthors=Apte SH, Baz A, Kelso A, Kienzle N |title=Interferon-gamma and interleukin-4 reciprocally regulate CD8 expression in CD8+ T cells |journal=Proc Natl Acad Sci U S A |volume=105 |issue= 45 |pages= 17475–80 |year= 2008 |pmid= 18988742 |doi= 10.1073/pnas.0809549105  | pmc=2580749 }}
| citations =  
*{{cite journal   |vauthors=Kay AB, Barata L, Meng Q, etal |title=Eosinophils and eosinophil-associated cytokines in allergic inflammation |journal=Int. Arch. Allergy Immunol. |volume=113 |issue= 1–3 |pages= 196–9 |year= 1997 |pmid= 9130521 |doi=10.1159/000237545 }}
*{{cite journal | author=Kay AB, Barata L, Meng Q, ''et al.'' |title=Eosinophils and eosinophil-associated cytokines in allergic inflammation. |journal=Int. Arch. Allergy Immunol. |volume=113 |issue= 1-3 |pages= 196-9 |year= 1997 |pmid= 9130521 |doi=  }}
*{{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=J. Allergy Clin. Immunol. |volume=107 |issue= 1 |pages= 22–30 |year= 2001 |pmid= 11149986 |doi=10.1067/mai.2001.111589 }}
*{{cite journal  | author=Marone G, Florio G, Petraroli A, de Paulis A |title=Dysregulation of the IgE/Fc epsilon RI network in HIV-1 infection. |journal=J. Allergy Clin. Immunol. |volume=107 |issue= 1 |pages= 22-30 |year= 2001 |pmid= 11149986 |doi=  }}
*{{cite journal   |vauthors=Marone G, Florio G, Triggiani M, etal |title=Mechanisms of IgE elevation in HIV-1 infection |journal=Crit. Rev. Immunol. |volume=20 |issue= 6 |pages= 477–96 |year= 2001 |pmid= 11396683 |doi=  10.1615/critrevimmunol.v20.i6.40}}
*{{cite journal | author=Marone G, Florio G, Triggiani M, ''et al.'' |title=Mechanisms of IgE elevation in HIV-1 infection. |journal=Crit. Rev. Immunol. |volume=20 |issue= 6 |pages= 477-96 |year= 2001 |pmid= 11396683 |doi=  }}
*{{cite journal  |vauthors=Maeda S, Yanagihara Y |title=[Inflammatory cytokines (IL-4, IL-5 and IL-13)] |journal=Nippon Rinsho |volume=59 |issue= 10 |pages= 1894–9 |year= 2001 |pmid= 11676128 |doi=  }}
*{{cite journal  | author=Maeda S, Yanagihara Y |title=[Inflammatory cytokines (IL-4, IL-5 and IL-13)] |journal=Nippon Rinsho |volume=59 |issue= 10 |pages= 1894-9 |year= 2001 |pmid= 11676128 |doi=  }}
*{{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= 263–9 |year= 2003 |pmid= 14561191 |doi=10.2174/1568010023344661 }}
*{{cite journal  | author=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= 263-9 |year= 2003 |pmid= 14561191 |doi=  }}
*{{cite journal  | author=Copeland KF |title=Modulation of HIV-1 transcription by cytokines and chemokines |journal=Mini Reviews in Medicinal Chemistry |volume=5 |issue= 12 |pages= 1093–101 |year= 2006 |pmid= 16375755 |doi=10.2174/138955705774933383 }}
*{{cite journal  | author=Copeland KF |title=Modulation of HIV-1 transcription by cytokines and chemokines. |journal=Mini reviews in medicinal chemistry |volume=5 |issue= 12 |pages= 1093-101 |year= 2006 |pmid= 16375755 |doi=  }}
*{{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= 293–8 |year= 2007 |pmid= 17389011 |doi= 10.1111/j.1399-0039.2007.00831.x }}
*{{cite journal  | author=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= 293-8 |year= 2007 |pmid= 17389011 |doi= 10.1111/j.1399-0039.2007.00831.x }}
*{{cite journal  |author1=Sokol CL |author2=Chu NQ |author3=Shuang Yu |author4=Simone Nish |author5=Terri Laufer |author6=Ruslan Medzhitov |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 |year= 2009 |pmid= 19465907 |doi= 10.1038/ni.1738  | pmc= 3252751 }}
}}
* {{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 = Nat. Immunol. | volume = 10 | issue = 7 | pages = 713–20 |date=July 2009 | pmid = 19465907 | doi = 10.1038/ni.1738 | url = | pmc = 3252751 }}
{{refend}}
{{refend}}


{{immunology-stub}}
==External links==
{{interleukins}}
* {{MeshName|Interleukin-4}}
 
* [http://antibody-antibodies.com/product37896-search-Interleukin_4_%28IL_4%29,_13.5kD,_Mouse,_recombinant.html Interleukin-4 from Gentaur] at [[Gentaur]]
[[Category:Immunology]]
* [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]]


{{SIB}}
{{PDB Gallery|geneid=3565}}
{{Interleukins}}
{{Interleukin receptor modulators}}
{{Portal bar|Molecular and cellular biology}}


{{WH}}
[[Category:Protein domains]]
{{WS}}
[[Category:Interleukins]]

Latest revision as of 15:57, 27 November 2018

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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Location (UCSC)n/an/a
PubMed searchn/an/a
Wikidata
View/Edit Human
Interleukin 4
File:PDB 1itm EBI.jpg
analysis of the solution structure of human interleukin 4 determined by heteronuclear three-dimensional nuclear magnetic resonance techniques
Identifiers
SymbolIL4
PfamPF00727
Pfam clanCL0053
InterProIPR002354
PROSITEPDOC00655
SCOP2int
SUPERFAMILY2int

The interleukin 4 (IL4, IL-4) is a cytokine that induces differentiation of naive helper T cells (Th0 cells) to Th2 cells. Upon activation by IL-4, Th2 cells subsequently produce additional IL-4 in a positive feedback loop. The cell that initially produces IL-4, thus inducing Th2 differentiation, has not been identified, but recent studies suggest that basophils may be the effector cell.[1] It is closely related and has functions similar to Interleukin 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 Th1 cells, macrophages, IFN-gamma, and dendritic cell 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.[7]

Discovery

This cytokine was co-discovered by Maureen Howard and William E. Paul[8] 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).[9]

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.[10]

Clinical significance

IL-4 also has been shown to drive mitogenesis, dedifferentiation, and metastasis in rhabdomyosarcoma.[11] IL-4, along with other Th2 cytokines, is involved in the airway inflammation observed in the lungs of patients with allergic asthma.[12]

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 Th2 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 VCAM-1 molecules (vascular cell adhesion molecule 1), promoting eosinophilic transmigration through endothelium, mucus secretion and T helper type 2 (Th2) 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.[13]

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. Many overexpression of IL-4R has been found in many types of cancer. Renal cells and glioblastoma modify 10,000-13,000 receptors per cell depending on tumor type.[14]

IL-4 can primitively motivate tumor cells and increase their apoptosis resistance by increasing tumor growth.[15]

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 angiotensin 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.[16]

HIV

IL-4 may also play a role in the infection and development of HIV disease. Auxiliary T-lymphocytes 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 Th2 cells. Increased IL-4 production by Th2 cells has been demonstrated in people infected with HIV.[17]

See also

References

  1. ↑ Sokol, C.L., Barton, G.M., Farr, A.G. & Medzhitov, R. (2008). "A mechanism for the initiation of allergen-induced T helper type 2 responses". Nat Immunol. 9 (3): 310–318. doi:10.1038/ni1558. PMC 3888112. PMID 18300366.
  2. ↑ Hershey GK, Friedrich MF, Esswein LA, Thomas ML, Chatila TA (December 1997). "The association of atopy with a gain-of-function mutation in the alpha subunit of the interleukin-4 receptor". N. Engl. J. Med. 337 (24): 1720–5. doi:10.1056/NEJM199712113372403. PMID 9392697. Lay summary – eurekalert.org.
  3. ↑ Jon Aster, Vinay Kumar, Abul K. Abbas; Nelson Fausto (2009). Robbins & Cotran Pathologic Basis of Disease (8th ed.). Philadelphia: Saunders. p. 54. ISBN 1-4160-3121-9.
  4. ↑ Maes T, Joos GF, Brusselle GG (September 2012). "Targeting interleukin-4 in asthma: lost in translation?". Am. J. Respir. Cell Mol. Biol. 47 (3): 261–70. doi:10.1165/rcmb.2012-0080TR. PMID 22538865.
  5. ↑ Chatila TA (October 2004). "Interleukin-4 receptor signaling pathways in asthma pathogenesis". Trends Mol Med. 10 (10): 493–9. doi:10.1016/j.molmed.2004.08.004. PMID 15464449.
  6. ↑ Carr C, Aykent S, Kimack NM, Levine AD (February 1991). "Disulfide assignments in recombinant mouse and human interleukin 4". Biochemistry. 30 (6): 1515–23. doi:10.1021/bi00220a011. PMID 1993171.
  7. ↑ 7.0 7.1 Walter MR, Cook WJ, Zhao BG, Cameron RP, Ealick SE, Walter RL, Reichert P, Nagabhushan TL, Trotta PP, Bugg CE (October 1992). "Crystal structure of recombinant human interleukin-4". J. Biol. Chem. 267 (28): 20371–6. PMID 1400355.
  8. ↑ Howard M, Paul WE (1982). "Interleukins for B lymphocytes". Lymphokine Res. 1 (1): 1–4. PMID 6985399.
  9. ↑ Yokota T, et al. (1986). "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". Proc. Natl. Acad. Sci. U.S.A. 83 (16): 5894–8. doi:10.1073/pnas.83.16.5894. PMC 386403. PMID 3016727.
  10. ↑ Bhattarai P, Thomas AK, Cosacak MI, Papadimitriou C, Mashkaryan V, Froc C, Reinhardt S, Kurth T, Dahl A, Zhang Y, Kizil C (2016). "IL4/STAT6 Signaling Activates Neural Stem Cell Proliferation and Neurogenesis upon Amyloid-β42 Aggregation in Adult Zebrafish Brain". Cell Reports. 17 (4): 941–8. doi:10.1016/j.celrep.2016.09.075. PMID 27760324.
  11. ↑ Hosoyama T, Aslam MI, Abraham J, Prajapati SI, Nishijo K, Michalek JE, Zarzabal LA, Nelon LD, Guttridge DC, Rubin BP, Keller C (May 2011). "IL-4R Drives Dedifferentiation, Mitogenesis, and Metastasis in Rhabdomyosarcoma". Clin Cancer Res. 17 (9): 2757–2766. doi:10.1158/1078-0432.CCR-10-3445. PMC 3087179. PMID 21536546.
  12. ↑ Gour N, Wills-Karp M (2015). "IL-4 and IL-13 signaling in allergic airway disease". Cytokine. 75 (1): 68–78. doi:10.1016/j.cyto.2015.05.014. PMC 4532591. PMID 26070934.
  13. ↑ Steinke, John W.; Borish, Larry (19 February 2001). "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. p. 66. doi:10.1186/rr40.
  14. ↑ Ul-Haq, Zaheer; Naz, Sehrish; Mesaik, M. Ahmed. "Interleukin-4 receptor signaling and its binding mechanism: A therapeutic insight from inhibitors tool box". Cytokine & Growth Factor Reviews. pp. 3–15. doi:10.1016/j.cytogfr.2016.04.002.
  15. ↑ Li, Z.; Jiang, J.; Wang, Z.; Zhang, J.; Xiao, M.; Wang, C.; Lu, Y.; Qin, Z. (1 November 2008). "Endogenous Interleukin-4 Promotes Tumor Development by Increasing Tumor Cell Resistance to Apoptosis". Cancer Research. 68 (21): 8687–8694. doi:10.1158/0008-5472.CAN-08-0449.
  16. ↑ Puri, Sachin; Joshi, Bharat H.; Sarkar, Chitra; Mahapatra, Ashok Kumar; Hussain, Ejaz; Sinha, Subrata (15 May 2005). "Expression and structure of interleukin 4 receptors in primary meningeal tumors". Cancer. 103 (10): 2132–2142. doi:10.1002/cncr.21008.
  17. ↑ Meyaard, L; Hovenkamp, E; Keet, IP; Hooibrink, B; de Jong, IH; Otto, SA; Miedema, F (15 September 1996). "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): 2712–8. PMID 8805678.

Further reading

External links

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