IL-9 and its Receptor: From Signal Transduction to Tumorigenesis

Catholic University of Louvain, Лувен-ла-Нев, Walloon, Belgium
Growth Factors (Impact Factor: 3.39). 01/2005; 22(4):207-15. DOI: 10.1080/08977190410001720879
Source: PubMed


IL-9 is a multifunctional cytokine secreted by TH2 lymphocytes. Besides its role during immune responses, its growth factor and antiapoptotic activities on multiple transformed cells suggest a potential role in tumorigenesis. Indeed, IL-9 overexpression induces thymic lymphomas in mice, and IL-9 production is associated with Hodgkin disease and HTLV-I transformed T cells in humans. IL-9 activities are mediated by a specific receptor chain that forms a heterodimeric receptor with the common gamma chain also involved in IL-2,4,7,15 and 21 signaling. The IL-9 receptor and common gamma chains associate with JAK1 and JAK3, respectively and trigger the STAT-1, -3 and -5, IRS and RAS-MAPK pathways. Moreover, in vitro, dysregulated IL-9 response can lead to autonomous cell growth and malignant transformation of lymphoid cells associated with constitutive activation of the Jak/STAT pathway.

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    • "It demonstrated pro-inflammatory activity and played a key role in the pathogenesis of atopic diseases and asthma [20]–[22]. Its activities are mediated via a heterodimeric receptor complex formed by the IL-9Rα chain, which associates with JAK1 and the IL-2Rγ chain, also known as γc (common γ chain), which associates with JAK3 [23]. JAK3 mutations are involved in the pathogenesis of NK/T cell lymphoma [24], [25]. "
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    ABSTRACT: Interleukin-9 (IL-9) is more functionally diverse than previously expected, especially with regards to lymphomagenesis. However, the relationship between IL-9 and the clinicopathological features of extranodal NK/T-cell lymphoma is less well established. Patients with this lymphoma in Sun Yat-Sen University Cancer Center between January 2003 and March 2013 were systematically reviewed in an intention-to-treat analysis. Baseline serum IL-9 levels were determined using sandwich enzyme-linked immunosorbent assays. A total of seventy-four patients were enrolled in this study. The mean concentration of serum IL-9 for all patients was 6.48 pg/mL (range: 1.38-51.87 pg/mL). Age, B symptoms and local lymph node involvement were found to be related to high serum IL-9 levels. Patients with low IL-9 levels tended to have higher rates of complete remission. Notably, the median progression-free survival (PFS) and overall survival (OS) were longer in the low IL-9 level group than in the high IL-9 level group (PFS: 68.7 months vs. 28.3 months, P<0.001; OS: 86 months vs. 42.8 months, P = 0.001). Multivariate analysis revealed independent prognostic factors for PFS. Similarly, high IL-9 levels (P = 0.003) and old age (P = 0.007) were independently predictive of shorter OS. Serum IL-9 is closely related to several clinical features, such as age, B symptoms and local lymph node involvement. It can also be a significant independent prognostic factor for extranodal NK/T-cell lymphoma, which suggests a role for IL-9 in the pathogenesis of this disease and offers new insight into potential therapeutic strategies.
    PLoS ONE 04/2014; 9(4):e94637. DOI:10.1371/journal.pone.0094637 · 3.23 Impact Factor
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    • "Furthermore, according to its growth/proliferative and anti-apoptotic activities on the different transformed cells, a potential role for this cytokine might be tumorigenesis.[34] In addition, over-expression of IL-9 induces thymic lymphomas in mice, and IL-9 production is associated with the Hodgkin disease and human T-lymphotropic virus type-1 transformed T-cells in human.[35] Nevertheless, this patient by herself is not affected by lymphoma. "
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    ABSTRACT: Background: Common variable immunodeficiency (CVID) is characterized by a deficiency in the immune system with a heterogeneous collection of disorders resulting in antibody deficiency and recurrent infections. T helper 17 (Th17) cells promote B-cell survival and synergize with the B-cell activating factor to induce their differentiation into the plasma cells. A sub-population of innate lymphoid cells (ILCs) also produces interleukin 17 (IL-17). This study aimed to measure the Th17 specific genes and ILCs counts in the CVID patients in comparison with control subjects. Materials and Methods: Total messenger ribonucleic acid (mRNA) was extracted from the whole blood samples of 10 CVID patients and 10 healthy individuals. IL-17, retinoic acid receptor-related orphan receptor C2 (RORC2), IL-23R, and IL-9 gene expression were measured using the quantitative reverse transcriptase polymerase chain reaction. Count of lineage negative/CD127+/CD90+ ILCs in the blood samples was performed by the flow cytometry method. Results: The transcript levels of IL-17 and RORC2 in CVID patients was strongly lower than control subjects (P = 0.049 and P = 0.046, respectively), but slight reduction in the IL-23R expression (P = 0.252) have seen in the CVID patients. Accordingly, the number of ILCs decreased significantly (P = 0.04). Interestingly, IL-9 mRNA level was more significantly in the CVID patients (P = 0.001). Conclusions: The results presented in this study show that the Th17 cell specific genes expression (as the determiner Th17 cells) and ILCs (another lymphoid source of IL-17) are decreased in patients with CVID and this could be an explanation for the defect of their humoral immune response. In addition, elevation of the IL-9 gene expression may shed a new light into the way toward the understanding of the mechanism of autoimmunity in the CVID patients.
    Journal of research in medical sciences 03/2014; 19(Suppl 1). · 0.65 Impact Factor
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    • "Notably, IL-9 overexpression induces thymic lymphomas in mice, and IL-9 production has an effect on Hodgkin’s disease and human T-lymphotropic virus type I (HTLV-I)-transformed T cells in humans. IL-9 activities also involve IL-2, -4, -7, -15 and -21 signaling, which is mediated by a specific receptor chain that forms a heterodimeric receptor with the common γ chain (2). The IL-9R and common γ chains associate with Janus kinase (JAK) 1 and JAK3 and trigger the signal transducer and activator of transcription (STAT)-1, -3 and -5, insulin receptor signaling (IRS) and RAS-mitogen-activated protein kinase (MAPK) pathways. "
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    ABSTRACT: Although interleukin-9 (IL-9) exhibits pleiotropic functions in the immune system, it remains a well-known cytokine in hematological malignancies. Previous cell culture and animal model studies have revealed that the Janus kinase-signal transducer and activator of transcription signaling pathway, which may be activated by a number of cytokines including IL-9, is critical in hematological malignancies. The current review summarizes the characterization of the biological activities of IL-9, highlights the clearly defined roles of the cytokine, and outlines questions with regard to the functions of IL-9 that require further exploration and their downstream signaling proteins, signal transducers and activators of transcription.
    Oncology letters 03/2014; 7(3):602-610. DOI:10.3892/ol.2013.1761 · 1.55 Impact Factor
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