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.[1] It is closely related and has functions similar to Interleukin 13.
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]
↑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. PMID18300366.CS1 maint: Multiple names: authors list (link)
↑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. PMID9392697. 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. ISBN1-4160-3121-9.CS1 maint: Multiple names: authors list (link)
↑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. PMID22538865.
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. PMID9130521.
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Maeda S, Yanagihara Y (2001). "[Inflammatory cytokines (IL-4, IL-5 and IL-13)]". Nippon Rinsho. 59 (10): 1894–9. PMID11676128.
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. PMID14561191.
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. PMID16375755.
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. PMID17389011.
1iti: THE HIGH RESOLUTION THREE-DIMENSIONAL SOLUTION STRUCTURE OF HUMAN INTERLEUKIN-4 DETERMINED BY MULTI-DIMENSIONAL HETERONUCLEAR MAGNETIC RESONANCE SPECTROSCOPY
