Abstract
Th17 and Th9 cells have been demonstrated to possess immune regulatory functions in malignant pleural effusion (MPE). However, whether IL-17 can affect differentiation and function of Th9 cells in MPE remains unknown. The objective of the present study was to explore the impact of IL-17 on the in vivo differentiation of Th9 cells in relation to Th2 cells in a murine model of MPE, and to explore whether IL-17 inhibits MPE formation via IL-9‒dependent mechanism. It was found that Th9 and Th2 cells were decreased in MPE from IL-17 -/- mice as compared with wild type mice. IL-17 deficiency inhibited Th9 and Th2 cell differentiation via suppressing transcription factors IRF4 and GATA-3, respectively. IL-17 deficiency enhanced MPE formation by promoting angiogenesis and proliferation of pleural tumors, and thus accelerated the death of mice bearing MPE. The in vivo administration of anti-IL-9 neutralizing mAb accelerated the death of WT mice; whereas administration of exogenous IL-9 improved the survival of IL-17 -/- mice. Our data provide the first definitive evidence that IL-17 promotes the differentiation of Th9 and Th2 cells in MPE. Our findings also demonstrate that IL-17 inhibits the formation of MPE and improves the survival of mice bearing MPE via an IL-9-dependent mechanism.
Highlights
IL-9, a member of the IL-2 cytokine family, is produced by naïve CD4+ T lymphocytes in response to IL-4 and TGF- (Dardalhon et al, 2008; Veldhoen et al, 2008)
We have demonstrated that IL-17 deficiency promotes angiogenesis and proliferation activity of pleural tumors as well as pleural vascular permeability, and promotes Malignant pleural effusion (MPE) formation in the animal models of MPE using IL-17 / mice (Lin et al, 2014)
In the previous study (Lin et al, 2014), we have demonstrated that more pleural tumor foci and bloody MPE are found in IL-17 / mice as compared with Wild type (WT) mice 14 days after intrapleural injection of LLC cells
Summary
IL-9, a member of the IL-2 cytokine family, is produced by naïve CD4+ T lymphocytes in response to IL-4 and TGF- (Dardalhon et al, 2008; Veldhoen et al, 2008). IL-9 has been suggested to possess a functional role in some malignant lymphomas, such as Hodgkin’s disease and large-cell anaplastic lymphoma (Fischer et al, 2003; Merz et al, 1991). It has been demonstrated that IL-9 plays a role during tumor genesis because dysregulated IL-9 response results in autonomous cell growth and malignant transformation of lymphoid cells associated with constitutive acti-. It has been well documented that CD4+ T cell dominance occurs in MPE. Naïve CD4+ T cells become activated and differentiate into effector T helper (Th) cell subgroups, depending on the antigens and cytokine microenvironment they encounter. Our previous studies have demonstrated that several subgroups of CD4+ T cells, such as regulatory T cells (Tregs) (Chen et al, 2005), IL-17–producing CD4+ T cells (Th17 cells) (Ye et al, 2010), IL-22–producing CD4+ T cells (Th22 cells)
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