Signal transduction by the interleukin-9 receptor
(1999)
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- Interleukin-9 (IL-9) is a pleiotropic TH2 cytokine involved in anti-parasite immunity, asthma and lymphoma development. It regulates survival, growth, and differentiation of target cells, such as lymphocytes and mast cells. The present work aimed at identifying intracellular signals triggered by the binding of IL-9 to its membrane receptor. <BR> This receptor is a complex composed of two proteins: the IL-9 receptor itself (IL-9R), and the γc chain. Both proteins are associated with a tyrosine kinase of the JAK family, JAK1 and JAK3, respectively. These enzymes, which are activated in the presence of IL-9, are most likely responsible for the phosphorylation a single IL-9R tyrosine that we identified by mutagenesis. Our data suggest that this phosphoryled amino-acid is recognized by three transcription factors of the STAT family; i.e. STAT1, STAT3 and STAT5. Based on the literature, receptor-associated STATs are activated by JAK kinases, dissociate from the receptor, dimerize and migrate to the nucleus, where they regulate gene transcription. We showed that most genes regulated but IL-9 are controlled by this pathways. It is the case if Lys-6A/E, a gene involved in lymphocyte activation. Some of these genes are regulated by a specific STAT factor, whereas others are equally induced via STAT1, STAT3 or STAT5. These observations provide an explanation for differences in gene regulation by IL-2, IL-3, IL-6, IL-9 and interferon γ in our system. <BR> Our results also indicated that STAT transcription factors play a key role in IL-9-medaited cell proliferation and inhibition of apoptosis induced by glucocorticoids. It is likely that these effects of IL0 are also mediated by regulation of genes, the nature of which is still unknown, however. Implication of STATs in cell survival and proliferation prompted us to investigate their activation in tumorigenic clones derived from IL-9 dependent cell lines. In two murine models established in our laboratory, we observed that constitutive STAT activation was associated with tumorgenesis. These models should help us to identify STAT-regulated genes involved in proliferation. Taken together, our results point to a role for STAT factors in lymphocytic oncogenesis. Future studies will have to determine whether STATs are useful target in lymphoma and leukemia therapy
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Demoulin, J.-B. (1999). Signal transduction by the interleukin-9 receptor. https://hdl.handle.net/2078.5/111279