IL-9 Signaling

Interleukin 9 (IL-9) is a TH2-type cytokine, a potent T-Cell and mast cell growth factor and enhances the production of IgE from B-Cells, and promote the proliferation and differentiation of hematopoietic progenitors. It is a T-Cell derived cytokine with various effects on a variety of cell types associated with allergic inflammation. IL-9 is a member of the 4-helix bundle cytokine family, which includes cytokines such as IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, and IL-15.IL-9 exerts its effects through a receptor that consists of two chains, the IL-9R-α (IL-9-specific α chain of IL-9 Receptor) associated with γ chain, also involved in IL-2, IL-4, IL-7, and IL-15 signaling. The receptor is expressed in membrane-bound and soluble forms. The pathways responsible for IL-9-induced proliferation were found to depend mainly on the activation of STAT5, on the recruitment of the IRS1 adaptor, and on the activation of the ERK/MAPK pathway.Upon IL-9 binding, the IL-9R associates with its co-receptor protein called γC. This induces the phosphorylation of the JAK1 and JAK3 tyrosine kinases. A single tyrosine residue of the IL-9R is then phosphorylated and acts as a docking site for 3 transcription factors of the STAT family, STAT1, 3 and 5, which become phosphorylated and migrate to the nucleus, where they activate the transcription of a number of genes.IL-9 transcriptionally upregulated BCL3 expression in T-Cells and mast cells. IL-9 stimulation was associated with an increase in p50 homodimers DNA binding activity, which was mimicked by stable BCL3 expression. IL-9 stimulation inhibited NF-κB-mediated transcription in response to TNF. Stimulation with IL-9 involves the recruitment of IRS1 and PI3K, which might also have a role in the biological activities of this factor (i.e. activates Akt pathway). IL-9 induces the expression of Cytokine Inducible SH2-containing protein (CIS), Suppressor of Cytokine Signaling-2 (SOCS2) and SOCS3 through the JAK/STAT pathway. This induction is rapid and transient. SOCS3 affects IL-9 signaling but neither CIS nor SOCS2 has an effect. A negative effect of SOCS3 is also found on several activities of IL-9, such as STAT activation, BCL3 induction and protection against corticoid-induced apoptosis.IL-9 potentiates the production of IgG, IgM, and IgE by normal human B-lymphocytes induced by IL-4. IL-9 also induces functional changes such as secretion of IL-6 by mast cell lines. IL-9 is also a potent regulator of the expression of protease genes like those belonging to the granzyme family. In the presence of IL-3, IL-9 enhances the proliferation of bone marrow mast cells. IL-9 synergises with Erythropoietin (Epo) and selectively supports a subpopulation of an early class of BFU-E that responds to IL-3. IL-9 induces the production of IL-6 by mast cells and some other cell types. IL-9 also stimulates the proliferation of fetal thymocytes and murine thymic lymphomas in response to IL-2. It also promotes the proliferation of some leukemia cell lines. Uncontrolled expression of IL-9 is involved in the development of certain types of T-Cell tumors. Recently IL-9 is reported as a candidate gene for asthma and to be associated with bronchial hyper responsiveness and elevated levels of total serum IgE.