IL9 Pathway
IL9 (Interleukin-9) is a pleiotropic cytokine secreted by activated T cells, mainly TH2 and TH9. Other cells like mast cells, Treg cells and TH17, innate lymphoid cells, NKT cells, and dendritic cells can also secrete IL9. IL9 generally play an important role in immune response, its major target include T-cell clones, hematopoietic progenitors, mast cells, B lymphocytes and immature neuronal cell lines. In addition, it may be involved in tumorigenesis (Ref.1).
IL9 is a member of the four-helix cytokine family that signals through the the two chain IL9 receptor that include the IL9RA (IL9–specific alpha chain) and the common gamma chain, that is shared by IL-2, IL-4, IL-7, IL-15 and IL-21 receptors. IL9R is expressed in membrane-bound and soluble forms. The major pathway believed to be responsible for IL9-induced proliferation includes the activation of STAT1, STAT3, and STAT5. IL9RA is constitutively bound to JAK1 and the gammac is constitutively bound to JAK3. JAK activation causes receptor autophosphorylation that further activates phosphorylation and homo/hetero dimerization of STATs. Activated STATs then translocate to the nucleus, where bind regulatory sequences to drive transcription of STAT-dependent genes (Ref.2 and 3). IL9 induces the expression of CIS, SOCS2 and SOCS3 through the JAK-STAT pathway (Ref.4).
IL9R signaling also activates ERK/MAPK pathway and insulin receptor Substrate (IRS)–PI3K pathway. IL9 also involves the recruitment of IRS–PI3K pathway, which is necessary for the IRS-1/2-mediated proliferative effect of IL9 but not through AKT (Ref.5). IL9 plays a significant role in the central nervous system (CNS). T cell differentiation and activation in autoimmune inflammation is the major function of IL9 in CNS (Ref.6). IL9 is also involved in asthma by regulating development of airway inflammation, hyper responsiveness and fibrosis. Thus, targeting the IL9 pathway may provide a new therapeutic modality for asthma (Ref.7).
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