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Interleukin 4


1BBN, 1BCN, 1CYL, 1HIJ, 1HIK, 1HZI, 1IAR, 1ITI, 1ITL, 1ITM, 1RCB, 2B8U, 2B8X, 2B8Y, 2B8Z, 2B90, 2B91, 2CYK, 2D48, 2INT, 3BPL, 3BPN, 3QB7, 4YDY, 5FHX

Identifiers Aliases IL4, BCGF-1, BCGF1, BSF-1, BSF1, IL-4, interleukin 4 External IDs OMIM: 147780 MGI: 96556 HomoloGene: 491 GeneCards: IL4
Gene location Human
Chr Chromosome 5 human
Band 5q311 Start 132,673,986 bp
End 132,682,676 bp
RNA expression pattern


More reference expression data
Orthologs Species Human Mouse Entrez
Ensembl
UniProt
RefSeq mRNA

NM_172348
NM_000589
NM_001354990

NM_021283

RefSeq protein

NP_000580
NP_758858
NP_001341919

NP_067258

Location UCSC Chr 5: 13267 – 13268 Mb Chr 11: 536 – 5362 Mb PubMed search Wikidata
Interleukin 4
analysis of the solution structure of human interleukin 4 determined by heteronuclear three-dimensional nuclear magnetic resonance techniques
Identifiers
Symbol IL4
Pfam PF00727
Pfam clan CL0053
InterPro IPR002354
PROSITE PDOC00655
SCOP 2int
SUPERFAMILY 2int

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 Th0 differentiation, has not been identified, but recent studies suggest that basophils may be the effector cell It is closely related and has functions similar to Interleukin 13

Contents

  • 1 Function
    • 11 Inflammation and wound repair
  • 2 Receptor
  • 3 Structure
  • 4 Discovery
  • 5 Animal studies
  • 6 Clinical significance
  • 7 Illnesses associated with IL-4
    • 71 Allergic diseases
    • 72 Tumors
    • 73 Nervous system
    • 74 HIV
  • 8 See also
  • 9 References
  • 10 Further reading
  • 11 External links

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

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

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

Structure

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

Discovery

This cytokine was co-discovered by Maureen Howard and William E Paul 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

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

Clinical significance

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

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

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

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

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

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

See also

  • STAT6

References

  • This article incorporates text from the public domain Pfam and InterPro IPR002354
  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000113520 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000000869 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:" 
  4. ^ "Mouse PubMed Reference:" 
  5. ^ Sokol, CL, Barton, GM, Farr, AG & Medzhitov, R 2008 "A mechanism for the initiation of allergen-induced T helper type 2 responses" Nat Immunol 9 3: 310–318 doi:101038/ni1558 PMID 18300366 CS1 maint: Multiple names: authors list link
  6. ^ 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:101056/NEJM199712113372403 PMID 9392697 Lay summary – eurekalertorg 
  7. ^ 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 CS1 maint: Multiple names: authors list link
  8. ^ 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:101165/rcmb2012-0080TR PMID 22538865 
  9. ^ Chatila TA October 2004 "Interleukin-4 receptor signaling pathways in asthma pathogenesis" Trends Mol Med 10 10: 493–9 doi:101016/jmolmed200408004 PMID 15464449 
  10. ^ 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:101021/bi00220a011 PMID 1993171 
  11. ^ a b 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 
  12. ^ Howard M, Paul WE 1982 "Interleukins for B lymphocytes" Lymphokine Res 1 1: 1–4 PMID 6985399 
  13. ^ 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 USA 83 16: 5894–8 doi:101073/pnas83165894 PMC 386403  PMID 3016727 
  14. ^ 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:101016/jcelrep201609075 PMID 27760324 
  15. ^ 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:101158/1078-0432CCR-10-3445 PMC 3087179  PMID 21536546 
  16. ^ Gour N, Wills-Karp M 2015 "IL-4 and IL-13 signaling in allergic airway disease" Cytokine 75 1: 68–78 doi:101016/jcyto201505014 PMC 4532591  PMID 26070934 
  17. ^ 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:101186/rr40 
  18. ^ 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:101016/jcytogfr201604002 
  19. ^ 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:101158/0008-5472CAN-08-0449 
  20. ^ 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:101002/cncr21008 
  21. ^ 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

  • Apte SH, Baz A, Kelso A, Kienzle N 2008 "Interferon-gamma and interleukin-4 reciprocally regulate CD8 expression in CD8+ T cells" Proc Natl Acad Sci U S A 105 45: 17475–80 doi:101073/pnas0809549105 PMC 2580749  PMID 18988742 
  • Kay AB, Barata L, Meng Q, et al 1997 "Eosinophils and eosinophil-associated cytokines in allergic inflammation" Int Arch Allergy Immunol 113 1–3: 196–9 doi:101159/000237545 PMID 9130521 
  • Marone G, Florio G, Petraroli A, de Paulis A 2001 "Dysregulation of the IgE/Fc epsilon RI network in HIV-1 infection" J Allergy Clin Immunol 107 1: 22–30 doi:101067/mai2001111589 PMID 11149986 
  • Marone G, Florio G, Triggiani M, et al 2001 "Mechanisms of IgE elevation in HIV-1 infection" Crit Rev Immunol 20 6: 477–96 doi:101615/critrevimmunolv20i640 PMID 11396683 
  • Maeda S, Yanagihara Y 2001 "" Nippon Rinsho 59 10: 1894–9 PMID 11676128 
  • Izuhara K, Arima K, Yasunaga S 2003 "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: 263–9 doi:102174/1568010023344661 PMID 14561191 
  • Copeland KF 2006 "Modulation of HIV-1 transcription by cytokines and chemokines" Mini reviews in medicinal chemistry 5 12: 1093–101 doi:102174/138955705774933383 PMID 16375755 
  • Olver S, Apte S, Baz A, Kienzle N 2007 "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: 293–8 doi:101111/j1399-0039200700831x PMID 17389011 
  • Sokol CL; Chu NQ; Shuang Yu; Simone Nish; Terri Laufer; Ruslan Medzhitov 2009 "Basophils function as antigen-presenting cells for an allergen-induced T helper type 2 response" Nature Immunology 10 7: 713–720 doi:101038/ni1738 PMC 3252751  PMID 19465907 
  • Sokol CL, Chu NQ, Yu S, Nish SA, Laufer TM, Medzhitov R July 2009 "Basophils function as antigen-presenting cells for an allergen-induced T helper type 2 response" Nat Immunol 10 7: 713–20 doi:101038/ni1738 PMC 3252751  PMID 19465907 

External links

  • Interleukin-4 at the US National Library of Medicine Medical Subject Headings MeSH
  • Interleukin-4 from Gentaur at Gentaur
  • Recombinant Human Interleukin-4 from Cornell University
  • Interleukin-4 from Allergy Glossary at Health On the Net Foundation
  • Molecular and cellular biology portal


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