Interleukin 4

IL4
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 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, Interleukin 4, IL-4
External IDs	MGI: 96556 HomoloGene: 491 GeneCards: IL4
Gene location (Human) Chr. Chromosome 5 (human) Band 5q31.1 Start 132,009,678 bp End 132,018,370 bp
Gene location (Mouse) Chr. Chromosome 11 (mouse)[1] Band 11 B1.3|11 31.97 cM Start 53,493,809 bp[1] End 53,509,496 bp[1]
Gene ontology Molecular function interleukin-4 receptor binding protein binding growth factor activity cytokine receptor binding cytokine activity Cellular component extracellular region extracellular space Biological process positive regulation of T cell differentiation dendritic cell differentiation negative regulation of endothelial cell apoptotic process negative regulation of complement-dependent cytotoxicity regulation of phosphorylation negative regulation of apoptotic process myeloid dendritic cell differentiation type 2 immune response B cell activation positive regulation of interleukin-13 production immune response B cell differentiation T-helper 2 cell cytokine production regulation of isotype switching negative regulation of transcription, DNA-templated negative regulation of epithelial cell migration regulation of signaling receptor activity cholesterol metabolic process positive regulation of B cell proliferation positive regulation of T cell proliferation T cell activation positive regulation of MHC class II biosynthetic process negative regulation of osteoclast differentiation positive regulation of transcription, DNA-templated positive regulation of transcription by RNA polymerase II positive regulation of isotype switching to IgE isotypes positive regulation of isotype switching to IgG isotypes regulation of immune response cytokine-mediated signaling pathway positive regulation of gene expression positive regulation of macroautophagy positive regulation of tyrosine phosphorylation of STAT protein activation of Janus kinase activity positive regulation of receptor-mediated endocytosis positive regulation of cold-induced thermogenesis negative regulation of neuroinflammatory response positive regulation of amyloid-beta clearance neuroinflammatory response positive regulation of cellular respiration positive regulation of ATP biosynthetic process Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 3565 16189 Ensembl ENSG00000113520 ENSMUSG00000000869 UniProt P05112 P07750 RefSeq (mRNA) NM_000589.4 NM_021283 RefSeq (protein) NP_000580 NP_758858 NP_001341919 NP_067258 Location (UCSC) Chr 5: 132.01 – 132.02 Mb Chr 11: 53.49 – 53.51 Mb PubMed search [2] [3]
Wikidata
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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
SCOP2	2int / SCOPe / SUPFAM
Available protein structures: Pfam   structures / ECOD   PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

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.^[4] 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.^[5]

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.^[6]

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.^[7][8]

Structure

IL-4 has a compact, globular fold (similar to other cytokines), stabilised by 3 disulphide bonds.^[9] One half of the structure is dominated by a 4 alpha-helix bundle with a left-handed twist.^[10] The helices are anti-parallel, with 2 overhand connections, which fall into a 2-stranded anti-parallel beta-sheet.^[10]

Evolution

IL-4 is closely related to IL-13, and both stimulate type 2 immunity.^[11] Genes of this family have also been found in fish, both in bony fish^[12][13] and cartilaginous fish;^[14] because at that evolutionary level they can't be distinguished as IL-4 or IL-13, they have been named IL-4/13.^[13]

Discovery

This cytokine was co-discovered by Maureen Howard and William E. Paul^[15] 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).^[16]

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.^[17]

Clinical significance

IL-4 has also been shown to drive mitogenesis, dedifferentiation, and metastasis in rhabdomyosarcoma.^[18] IL-4, along with other Th2 cytokines, is involved in the airway inflammation observed in the lungs of patients with allergic asthma.^[19]

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.^[20]

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 10000–13000 receptors per cell depending on tumor type.^[21]

IL-4 can primitively motivate tumor cells and increase their apoptosis resistance by increasing tumor growth.^[22]

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.^[23]

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.^[24]

See also

• STAT6

References

• This article incorporates text from the public domain Pfam and InterPro: IPR002354

Further reading

External links

• Interleukin-4 at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Interleukin-4 from Gentaur
• Recombinant Human Interleukin-4 from Cornell University
• Interleukin-4 from Allergy Glossary at Health On the Net Foundation
• Overview of all the structural information available in the PDB for UniProt: P05112 (Interleukin-4) at the PDBe-KB.