IL-7 Signaling Pathway

Interleukin-7 (IL-7) is an immune regulatory cytokine of the IL-2 superfamily. In humans, it is produced by a range of cells including thymic and bone marrow stroma, intestinal epithelial cells, keratinocytes, hepatic tissues, peripheral blood dendritic cells, follicular dendritic cells, endothelial cells, smooth muscle and fibroblasts. The active form of IL-7 in humans is a single chain 25 kDa glycoprotein which shows 81% homology with mouse proteins.IL-7 is essential for T-cell survival and proliferation. In mice it is also indispensable for B-cell development, but is less essential for B-cell development in humans. It also has a major impact on the homeostasis, differentiation, and activity of mature T-cells.IL-7 binds to a specific receptor IL-7R. The receptor is a heterodimer, contains a specific alpha subunit, IL-7Rα, and a common gamma chain, IL-7Rγc which is also shared by the IL-2, IL-4, IL-9, IL-15, and IL-21 cytokine receptors. Both receptor components are members of the cytokine receptor family. IL-7 can bind IL7Rα alone with low affinity, and to the combined complex with high-affinity. IL-7Rα is expressed during all early stages of T cell development, but not in double-positive T cells and activated T cells. IL-7Rα is expressed in mouse and human developing B cells, but it is downregulated during their maturation. The signaling pathways activated upon IL-7 binding to the receptor complex are JAK/STAT, SRC kinase and PI-3 kinase pathways.Binding of IL-7 to IL-7R leads to activation of JAK1 and JAK3 tyrosine kinases which phosphorylate STAT transcription factors. STAT1 plays a growth inhibitory effect and represses the expression of c-myc and c-jun oncogenes. STAT5 has anti-apoptotic activity by regulating the expression of several BCL-2 family members. JAK3 also activates NFAT transcription factor which has cell survival effect by increasing the expression of BCL-2 protein. IL-7 also activates SRC kinases Lyn and Fyn, which have a non-essential function in cell proliferation.The PI-3 kinase pathway has been demonstrated to be important for B and T cell development. In human T cells, JAK3 was found associated with the p85 subunit of PI-3 kinase. The activation of PI-3 kinase was essential for the IL-7-mediated survival and proliferation of human T cell precursors. AKT is a key downstream target of PI-3 kinase, which regulates numerous pro- and anti-apoptotic genes and inhibits by phosphorylation the BAD protein translocation from cytoplasm into the nucleus, thereby prevents the cell from apoptosis.