Summary: Interleukin 4
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Interleukin 4 Edit Wikipedia article
|, BCGF-1, BCGF1, BSF-1, BSF1, IL-4, interleukin 4|
|RNA expression pattern|
analysis of the solution structure of human interleukin 4 determined by heteronuclear three-dimensional nuclear magnetic resonance techniques
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.
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.
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.
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.
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.
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.
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.
- "Human PubMed Reference:".
- "Mouse PubMed Reference:".
- 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. PMID 18300366.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Howard M, Paul WE (1982). "Interleukins for B lymphocytes". Lymphokine Res. 1 (1): 1–4. PMID 6985399.
- 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 . PMID 3016727.
- 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.
- 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 . PMID 21536546.
- 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 . PMID 26070934.
- 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:10.1073/pnas.0809549105. PMC . 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:10.1159/000237545. 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:10.1067/mai.2001.111589. 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:10.1615/critrevimmunol.v20.i6.40. PMID 11396683.
- Maeda S, Yanagihara Y (2001). "[Inflammatory cytokines (IL-4, IL-5 and IL-13)]". 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:10.2174/1568010023344661. PMID 14561191.
- Copeland KF (2006). "Modulation of HIV-1 transcription by cytokines and chemokines". Mini reviews in medicinal chemistry. 5 (12): 1093–101. doi:10.2174/138955705774933383. 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:10.1111/j.1399-0039.2007.00831.x. 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:10.1038/ni.1738. PMC . 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:10.1038/ni.1738. PMC . PMID 19465907.
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This tab holds annotation information from the InterPro database.
InterPro entry IPR002354
Cytokines are protein messengers that carry information from cell to cell [PUBMED:8151703]. Interleukin is one such molecule, and participates in several B-cell activation processes: e.g., it enhances production and secretion of IgG1 and IgE [PUBMED:3083412]; it induces expression of class II major histocompatability complex (MHC) molecules on resting B-cells; and it regulates expression of the low affinity Fc receptor for IgE on lymphocytes and monocytes. Interleukin-4 (IL4), which this entry represents, has a compact, globular fold (similar to other cytokines), stabilised by 3 disulphide bonds [PUBMED:1993171]. One half of the structure is dominated by a 4 alpha-helix bundle with a left-handed twist [PUBMED:1400355]. The helices are anti-parallel, with 2 overhand connections, which fall into a 2-stranded anti-parallel beta-sheet [PUBMED:1400355].
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Cellular component||extracellular region (GO:0005576)|
|Molecular function||growth factor activity (GO:0008083)|
|interleukin-4 receptor binding (GO:0005136)|
|Biological process||immune response (GO:0006955)|
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
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Cytokines are regulatory peptides that can be produced by various cells for communicating and orchestrating the large multicellular system. Cytokines are key mediators of hematopoiesis, immunity, allergy, inflammation, tissue remodeling, angiogenesis, and embryonic development . This superfamily includes both the long and short chain helical cytokines.
The clan contains the following 29 members:CNTF CSF-1 EPO_TPO Flt3_lig GCSF GM_CSF Hormone_1 IFN-gamma IL10 IL11 IL12 IL13 IL15 IL2 IL22 IL23 IL28A IL3 IL34 IL4 IL5 IL6 IL7 Interferon Leptin LIF_OSM PRF SCF TSLP
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1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
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This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
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|Seed source:||Pfam-B_833 (release 2.1)|
|Number in seed:||14|
|Number in full:||84|
|Average length of the domain:||102.50 aa|
|Average identity of full alignment:||35 %|
|Average coverage of the sequence by the domain:||71.02 %|
|HMM build commands:||
build method: hmmbuild --amino -o /dev/null HMM SEED
search method: hmmsearch -Z 26740544 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||17|
|Download:||download the raw HMM for this family|
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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the More....
This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.
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Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
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The tree shows the occurrence of this domain across different species. More...
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For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
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Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
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There are 3 interactions for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the IL4 domain has been found. There are 27 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.
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