IL-4 signaling pathway

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. IL-4 is primarily involved in promoting the differentiation and proliferation of T helper 2 (TH2) cells and the synthesis of immunoglobulin E (IgE). Apart from its role in allergic responses including asthma, IL-4 was also found to regulate retinal progenitor proliferation, rod photoreceptor differentiation, cholinergic and GABAergic amacrine differentiation and neuroprotection and survival. 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. 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. Both these receptor complexes comprise of a common IL4Rα (CD124) subunit, which is also the functional receptor chain. Type I IL-4 receptor is formed by the interaction of IL4Rα subunit with IL-2γc (CD132). Type II IL-4 receptor is formed by the interaction of IL-4Rα subunit with IL-13Rα. 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. 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. Please access this pathway at [http://www.netpath.org/netslim/IL_4_pathway.html NetSlim] database. If you use this pathway, please cite the following paper: Kandasamy, K., Mohan, S. S., Raju, R., Keerthikumar, S., Kumar, G. S. S., Venugopal, A. K., Telikicherla, D., Navarro, J. D., Mathivanan, S., Pecquet, C., Gollapudi, S. K., Tattikota, S. G., Mohan, S., Padhukasahasram, H., Subbannayya, Y., Goel, R., Jacob, H. K. C., Zhong, J., Sekhar, R., Nanjappa, V., Balakrishnan, L., Subbaiah, R., Ramachandra, Y. L., Rahiman, B. A., Prasad, T. S. K., Lin, J., Houtman, J. C. D., Desiderio, S., Renauld, J., Constantinescu, S. N., Ohara, O., Hirano, T., Kubo, M., Singh, S., Khatri, P., Draghici, S., Bader, G. D., Sander, C., Leonard, W. J. and Pandey, A. (2010). NetPath: A public resource of curated signal transduction pathways. <i>Genome Biology</i>. 11:R3.

IL-4（白介素-4）是一种由129个氨基酸组成的糖蛋白，其分子量为20kDa。IL-4与IL-13由CD4+细胞产生，并表现出显著的功能重叠。这两种细胞因子在促进过敏性反应中发挥着至关重要的作用。IL-4主要参与促进辅助性T细胞2（TH2）细胞的分化和增殖，以及免疫球蛋白E（IgE）的合成。除了在哮喘等过敏性反应中的作用外，IL-4还被发现能够调节视网膜祖细胞的增殖、棒状细胞视杆神经节细胞的分化、胆碱能和GABA能的神经节细胞分化以及神经保护和存活。IL-4还在包括阿尔茨海默病、多发性硬化症、实验性自身免疫性脑炎在内的多种神经系统疾病中显示出调节作用。此外，它还被发现能够缓解炎症性和神经性疼痛。IL-4通过与其两个细胞表面受体复合物——I型IL4受体和II型IL4受体相互作用来发挥其生物学活性。这两个受体复合物均包含一个共同的IL4Rα（CD124）亚基，该亚基也是功能性的受体链。I型IL4受体由IL4Rα亚基与IL-2γc（CD132）相互作用形成。II型IL4受体由IL4Rα亚基与IL-13Rα相互作用形成。IL-4与其受体的相互作用导致受体二聚化和激活。I型受体激活JAK1和3，这些酶与受体亚基相关联。激活的JAK磷酸化受体胞浆尾部的酪氨酸残基，这些残基随后作为多种适配器或信号分子的停靠位点，包括STAT6。激活的STAT6二聚化，转移至细胞核，并转录激活对IL-4反应的基因。IL4在过敏性疾病的许多关键功能，包括TH2细胞分化、气道高反应性、粘液细胞化生和IgE合成，都依赖于STAT6的激活。其他磷酸化的酪氨酸残基与具有磷酸酪氨酸结合（PTB）基序的蛋白质结合，包括IRS蛋白。这导致IRS蛋白的磷酸化，进而可以通过与PI3K的p85亚基或Ras/Raf/MEK/ERK级联的相互作用，激活PI3K/AKT级联或Ras/Raf/MEK/ERK级联。PI3K/AKT通路被认为在多种IL-4反应性细胞类型（包括T和B淋巴细胞以及自然杀伤细胞）的生长和存活信号中发挥作用。请访问[http://www.netpath.org/netslim/IL_4_pathway.html NetSlim]数据库以获取此通路信息。如果使用此通路，请引用以下论文：Kandasamy, K.，Mohan, S. S.，Raju, R.，Keerthikumar, S.，Kumar, G. S. S.，Venugopal, A. K.，等. (2010). NetPath: A public resource of curated signal transduction pathways. <i>Genome Biology</i>. 11:R3.