IL-4 is a glycoprotein which is composed of 129 amino acids and has a molecular weight of 20kDa. IL-4 and IL-13 are produced by CD4+ cells and exhibit significant functional overlap. Both these cytokines play a critical role in the promotion of allergic responses (1). IL-4 is primarily involved in promoting the differentiation and proliferation of T helper 2 (TH2) cells and the synthesis of immunoglobulin E (IgE) (2,3). Apart from its role in allergic responses including asthma, IL-4 was also found to regulate retinal progenitor proliferation, rod photoreceptor differentiation (4), cholinergic and GABAergic amacrine differentiation (5,6) and neuroprotection and survival (7,8). IL-4 was also found to have regulatory effects in a number of neurological diseases including Alzheimer's disease, Multiple sclerosis, Experimental autoimmune encephelitis. It was also found to relieve inflammatory and neuropathic pain (9,10).

IL-4 is capable of exerting its biological activities through interaction with two cell surface receptor complexes - Type I IL4 receptor and Type II IL4 Receptor (11). Both these receptor complexes comprise of a common IL4Ralpha (CD124) subunit, which is also the functional receptor chain. Type I IL-4 receptor is formed by the interaction of IL4Ralpha subunit with IL-2gammac (CD132) (12,13,14). Type II IL-4 receptor is formed by the interaction of IL-4Ralpha subunit with IL-13Ralpha1 (15,16).

Interaction of IL-4 with its receptor results in receptor dimerization and activation. The Type I receptors activates JAK1 and 3, which are associated with the receptor subunits. The activated JAK phosphorylates tyrosine residues the cytoplasmic tails of the receptor which then serves as docking sites for a number of adaptor or signaling molecules including STAT6 (12,16). Activated STAT6 dimerizes, translocated to the nucleus and transcriptionally actives genes responsive to IL-4. Many of the key functions of IL4 allergic disorders, including TH2 cell differentiation, airway hyper responsiveness, mucus cell metaplasia and IgE synthesis are dependent on STAT6 activation.

Other phosphorylated tyrosine residue bind to proteins with phospho-tyrosine binding (PTB) motifs including IRS proteins. This results in the phosphorylation of the IRS proteins, which can then potentially activate the PI3K/AKT cascade by binding to the p85 subunit of PI3K or the Ras/Raf/MEK/ERK cascade. The PI3K/AKT pathway is thought to mediate the growth and survival signals in multiple IL-4 responsive cell types including T- and B- lymphocytes and natural killer cells (17,18,19).

References

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10. Vale ML, Marques JB, Moreira CA, Rocha FA, Ferreira SH, Poole S, Cunha FQ, Ribeiro RA. Antinociceptive effects of interleukin-4, -10, and -13 on the writhing response in mice and zymosan-induced knee joint incapacitation in rats. Pharmacol Exp Ther. 2003 Jan;304(1):102-8.

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14. Russell SM, Keegan AD, Harada N, Nakamura Y, Noguchi M, Leland P, Friedmann MC, Miyajima A, Puri RK, Paul WE, et al. Interleukin-2 receptor gamma chain: a functional component of the interleukin-4 receptor. Science. 1993 Dec 17;262(5141):1880-3.

15. Mueller TD, Zhang JL, Sebald W, Duschl A. Structure, binding, and antagonists in the IL-4/IL-13 receptor system. Biochim Biophys Acta. 2002 Nov 11;1592(3):237-50.

16. Kelly-Welch AE, Hanson EM, Boothby MR, Keegan AD. Interleukin-4 and interleukin-13 signaling connections maps. Science. 2003 Jun 6;300(5625):1527-8.

17. Sun XJ, Wang LM, Zhang Y, Yenush L, Myers MG Jr, Glasheen E, Lane WS, Pierce JH, White MF. Role of IRS-2 in insulin and cytokine signalling. Nature. 1995 Sep 14;377(6545):173-7.

18. Keegan AD, Nelms K, White M, Wang LM, Pierce JH, Paul WE. An IL-4 receptor region containing an insulin receptor motif is important for IL-4-mediated IRS-1 phosphorylation and cell growth. Cell. 1994 Mar 11;76(5):811-20.

19. Wurster AL, Withers DJ, Uchida T, White MF, Grusby MJ. Stat6 and IRS-2 cooperate in interleukin 4 (IL-4)-induced proliferation and differentiation but are dispensable for IL-4-dependent rescue from apoptosis. Mol Cell Biol. 2002 Jan;22(1):117-26.