IL-9 and its receptor: From signal transduction to tumorigenesis
ABSTRACT 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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ABSTRACT: Severe asthma afflicts only a small portion of the population of asthmatics; however, due to the severity of the disease, treatment of these patients generates disproportionately high costs, which account for as much as spend for treatment of all other asthmatics. This issue gains even more importance since currently available medications are often not sufficient to treat or even dampen the inflammatory response in the airways of severe asthmatics. Whereas mild-to-moderate asthma is characterized by reversibility of airway obstruction, severe asthma frequently includes a degree of fixed airflow limitation and corticosteroid refractoriness. In contrast to mild-to-moderate asthma, the inflammatory response in the airways appears to be much more complex including neutrophils as the dominating leukocyte subpopulation. A plethora of neutrophil-derived mediators and enzymes appears to perpetuate or aggravate the inflammatory response and its pathophysiologic consequences by forming several positive feedback loops. Although neutrophil infiltration into the airways is a common feature of acute asthma exacerbations, these cells are observed in the airways of severe asthmatics in the absence of bacterial infections. Since the identification of T helper 17 (TH17) cells in airway infiltrates of severe asthmatics, TH17 cells are also implicated in the immunopathology of the disease. By secreting interleukin 17A TH17 cells are able to induce the airway epithelial cell production of IL-8, the most potent chemoattractant for neutrophils. However, understanding the role of these cells within the context of the immunopathology of severe asthma is just in the fledging stages. This review aims at summarizing the actual knowledge on the immunopathologic mechanisms underlying this disease.Immunology Endocrine & Metabolic Agents - Medicinal Chemistry (Formerly Current Medicinal Chemistry - Immunology Endocrine & Metabolic Agents) 12/2009; 9(4-9(4)):234-45. DOI:10.2174/187152209790773039
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ABSTRACT: Constitutive activation of the JAK-STAT pathway is frequent in cancer and contributes to oncogenesis. Here, we took advantage of the Ba/F3 cell line, a murine proB cell line dependent on IL-3 for growth, to analyse mechanisms of constitutive STAT activation in vitro. Cytokine-independent and tumorigenic Ba/F3 cell lines were derived from a two-step selection process. Cells transfected with a defective IL-9 receptor acquire IL-9 responsiveness during a first step of selection, and progress after a second selection step to autonomously growing tumorigenic cells. Microarray analysis pointed to JAK1 overexpression as a key genetic event in this transformation. Overexpression of JAK1 not only increased the sensitivity to IL-9 but also allowed a second selection step toward cytokine-independent growth with constitutive STAT activation. This progression was dependent on a functional FERM and kinase JAK1 domain. Similar results were observed after JAK2, JAK3 and TYK2 overexpression. All autonomous cell lines showed an activation of STAT5, ERK1-2 and AKT but only TYK2-overexpressing cell lines showed a constitutive activation of STAT3. Thus, JAK overexpression can be considered as one of the oncogenic events leading to the constitutive activation of the JAK-STAT pathway.Oncogene 04/2008; 27(11):1511-9. DOI:10.1038/sj.onc.1210800 · 8.56 Impact Factor
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ABSTRACT: The histone acetyltransferases (HATs) of the MYST family are highly conserved in eukaryotes and carry out a significant proportion of all nuclear acetylation. These enzymes function exclusively in multisubunit protein complexes whose composition is also evolutionarily conserved. MYST HATs are involved in a number of key nuclear processes and play critical roles in gene-specific transcription regulation, DNA damage response and repair, as well as DNA replication. This suggests that anomalous activity of these HATs or their associated complexes can easily lead to severe cellular malfunction, resulting in cell death or uncontrolled growth and malignancy. Indeed, the MYST family HATs have been implicated in several forms of human cancer. This review summarizes the current understanding of these enzymes and their normal function, as well as their established and putative links to oncogenesis.Oncogene 09/2007; 26(37):5395-407. DOI:10.1038/sj.onc.1210608 · 8.56 Impact Factor