IL-9 Pathway
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IL-9 Pathway

IL-9 (Interleukin-9) is a TH2-type cytokine first described in the mouse as a potent T-Cell and mast cell growth factor. IL-9 has been reported to be a T-Cell derived cytokine with various effects on a variety of cell types associated with allergic inflammation. IL-9 has been shown to stimulate the proliferation of activated T-Cells, enhance the production of IgE from B-Cells, and promote the proliferation and differentiation of mast cells and hematopoietic progenitors. 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. Human IL-9 consists of a 14kDa glycoprotein whose mature form is composed of 144 amino acids along with a signal sequence of 18 amino acids. The IL-9 protein contains a high proportion of cationic amino acid residues, 10 cysteines and has 4 N-linked glycosylation sites. The human IL-9 gene has been shown to reside within the TH2 cytokine cluster in the region q31-35 on chromosome-5. This region, found on the long arm of the chromosome, has also been shown to contain the closely linked genes encoding for IL-3, IL-4, IL-5 and GMCSF . IL-9 gene is composed of five exons and four introns over approximately 4 kb. The 5’ flanking regions of human gene have shown specific binding sequences for the Activating Protein-1 and Activating Protein-2 transcription factors. The 5’ regulatory region of the IL-9 gene was found to contain sequences also seen in similar regions of IL-1, IL-2, IL-3, IL-4, IL-5, IL-6 and GMCSF genes, suggesting common regulatory mechanisms (Ref.1).

IL-9 exerts its effects through a receptor that consists of two chains, the IL-9RAlpha (IL-9-specific Alpha chain of IL-9 Receptor) associated with Gamma chain, also involved in IL-2, IL-4, IL-7, and IL-15 signaling. The human IL-9R gene consists of 10 exons spread over approximately 13.7 kb of DNA. 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 (Signal Transducer and Activator of Transcription-5), on the recruitment of the IRS1 (Insulin receptor substrate-1) adaptor, and on the activation of the ERK (Extracellular Signal Regulated Kinases) MAPK (Mitogen-Activated Protein Kinase) pathway (Ref.2).

Upon IL-9 binding, the IL-9R associates with its co-receptor protein called GammaC. This induces the phosphorylation of the JAK1 (Janus Kinase-1) and JAK3 (Janus Kinase-3) tyrosine kinases, which are associated with IL-9R and GAlpha-C, respectively. 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, STAT3 and STAT5, which become phosphorylated and migrate to the nucleus, where they activate the transcription of a number of genes (Ref.3).

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-KappaB (Nuclear Factor-KappaB) mediated transcription in response to TNF (Tumor Necrosis Factor) (Ref.4). Stimulation with IL-9 involves the recruitment of IRS1 and PI3K (Phosphoinositide-3 Kinase), which might also have a role in the biological activities of this factor (i.e. activates Akt pathway). IL-9 induces the expression of CIS (Cytokine Inducible SH2-containing protein), SOCS2 (Suppressor of Cytokine Signaling-2) 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 Epo (Erythropoietin) 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. IL-9 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 has been reported as a candidate gene for asthma and to be associated with bronchial hyper responsiveness and elevated levels of total serum IgE.