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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 Th2 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.
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.
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.
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).
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.
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 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.
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.
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.
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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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 386403. 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 3087179. 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 4532591. PMID 26070934.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- 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 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:10.1159/000237545. PMID 9130521.
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- 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 3252751. PMID 19465907.
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- 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