IL9 leads to airway inflammation by inducing IL13 expression in airway epithelial cells

Yale University, New Haven, Connecticut, United States
International Immunology (Impact Factor: 2.54). 02/2007; 19(1):1-10. DOI: 10.1093/intimm/dxl117
Source: PubMed


Constitutive expression of IL9 in the lungs of transgenic (Tg) mice resulted in an asthma-like phenotype consisting of lymphocytic and eosinophilic lung inflammation, mucus hypersecretion and mast cell hyperplasia. Several T(h)2 cytokines including IL4, IL5 and IL13 were expressed in the lung in response to Tg IL9. IL13 was absolutely necessary for the development of lung pathology. To understand how IL9 induces IL13-dependent lung inflammation and mucus production, we sought the IL13-producing cells. Surprisingly, we found that the absence of T cells and B cells in recombinase-activating gene 1 (RAG1)-deficient IL9 Tg mice enhanced lung inflammation and dramatically enhanced IL13 production. In addition, the lack of mast cells or eosinophils in IL9 Tg mice did not affect IL13 levels in the lung. In situ hybridization for IL13 on lung sections from RAG1-/- IL9 Tg mice revealed that airway epithelial cells were the major IL13-producing cell type. Our results implicate the lung epithelium as a potentially important source of inflammatory cytokines in asthma.

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Available from: Richard A Flavell, Oct 01, 2015
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    • "IL-9 is a pleiotropic Th2 cytokine released by a subset of CD4+ cells designated Th9 cells [12], [13] and has been identified as a candidate cytokine for asthma pathogenesis [14]. In murine models IL-9 stimulates mucin transcription and goblet cell hyperplasia [15] and by over-expressing IL-9 in the lungs of a transgenic mouse model it also induced IL-13 production from airway epithelial cells [16]. It is still unclear whether the role of IL-9 is that of a dominant cytokine or one of a helper cytokine in asthma. "
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    ABSTRACT: Asthma is a chronic inflammatory disease characterised by airways remodelling. In mouse models IL-9 and IL-13 have been implicated in airways remodelling including mucus hypersecretion and goblet cell hyperplasia. Their role, especially that of IL-9, has been much less studied in authentic human ex vivo models of the bronchial epithelium from normal and asthmatic children. We assessed the effects of IL-9, IL-13 and an IL-9/IL-13 combination, during differentiation of bronchial epithelial cells from normal (n = 6) and asthmatic (n = 8) children. Cultures were analysed for morphological markers and factors associated with altered differentiation (MUC5AC, SPDEF and MMP-7). IL-9, IL-9/IL-13 combination and IL-13 stimulated bronchial epithelial cells from normal children had fewer ciliated cells [14.8% (SD 8.9), p = 0.048, 12.4 (SD 6.1), p = 0.016 and 7.3% (SD 6.6), p = 0.031] respectively compared with unstimulated [(21.4% (SD 9.6)]. IL-9 stimulation had no effect on goblet cell number in either group whereas IL-9/IL-13 combination and IL-13 significantly increased goblet cell number [24.8% (SD 8.8), p = 0.02), 32.9% (SD 8.6), p = 0.007] compared with unstimulated normal bronchial cells [(18.6% (SD 6.2)]. All stimulations increased MUC5AC mRNA in bronchial epithelial cells from normal children and increased MUC5AC mucin secretion. MMP-7 localisation was dysregulated in normal bronchial epithelium stimulated with Th2 cytokines which resembled the unstimulated bronchial epithelium of asthmatic children. All stimulations resulted in a significant reduction in transepithelial electrical resistance values over time suggesting a role in altered tight junction formation. We conclude that IL-9 does not increase goblet cell numbers in bronchial epithelial cell cultures from normal or asthmatic children. IL-9 and IL-13 alone and in combination, reduce ciliated cell numbers and transepithelial electrical resistance during differentiation of normal epithelium, which clinically could inhibit mucociliary clearance and drive an altered repair mechanism. This suggests an alternative role for IL-9 in airways remodelling and reaffirms IL-9 as a potential therapeutic target.
    PLoS ONE 05/2013; 8(5):e61023. DOI:10.1371/journal.pone.0061023 · 3.23 Impact Factor
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    • "The division of labor between these subsets is still unclear. Previous experiments have suggested that IL-9 promotes type 2 cytokine production by innate lymphoid cells in the lung (Wilhelm et al., 2011) and IL-13-deficiency inhibits the allergic inflammation initiated by an IL-9 transgene (Temann et al., 2007). This was recapitulated in our studies showing that blockade of IL-13 diminished inflammation in Th9 cell recipient mice. "
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    ABSTRACT: Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine important for the initiation and development of T helper (Th2) cell-mediated allergic inflammation. In this study, we identified a positive association between interleukin-9 (IL-9) and TSLP concentration in the serum of infants with atopic dermatitis. In primary cell cultures, the addition of TSLP led to an increase in IL-9 production from human and mouse Th9 cells, and induced an increase in signal transducer and activator of transcription 5 (STAT5) activation and binding to the Il9 promoter. In vivo, use of an adoptive transfer model demonstrated that TSLP promoted IL-9-dependent, Th9 cell-induced allergic inflammation by acting directly on T cells. Moreover, transgenic expression of TSLP in the lung stimulated IL-9 production in vivo, and anti-IL-9 treatment attenuated TSLP-induced airway inflammation. Together, our results demonstrate that TSLP promotes Th9 cell differentiation and function and define a requirement for IL-9 in TSLP-induced allergic inflammation.
    Immunity 01/2013; 38(2). DOI:10.1016/j.immuni.2013.01.007 · 21.56 Impact Factor
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    • "All other Th cytokines depend on IL-13 to induce MCM and IL-13 acts, not through intermediate inflammatory cells, but on structural cells within the lung, likely the airway epithelium itself [40]. The potency of IL-13 is shown, requiring its complete blockade for a significant reduction in mucus production [41], [42]. "
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    ABSTRACT: Mucous cell metaplasia (MCM), defined by the appearance of mucous cells in airways where mucous cells were not present, is a consistent pathologic characteristic in the peripheral airways of bronchial asthma. Under mild inflammatory conditions MCM occurs as a result of pre-existing airway epithelial cells (AECs) starting to express mucin genes and differentiating into mucous cells. Under extensive inflammatory responses, AECs proliferate, and the development of MCM involves the differentiation of pre-existing and proliferating cells into mucous cells. Epithelial cell numbers per mm basal lamina are increased by approximately 30%. IL-13 is the central cytokine that is responsible for MCM in asthma through GABA-R- and STAT6-mediated mechanisms involving the calcium-activated chloride channel CLCA. IL-13 is also responsible for the proliferation of AECs by causing cells to produce TGFalpha that acts on the epidermal growth factor (EGF) receptor. Normally, resolution of MCM involves two distinct mechanisms. 1) Some of the metaplastic mucous cells stop the synthesis of mucus and dedifferentiate into Clara or serous cells to reconstitute the epithelium. 2) When proliferation of epithelial cells had occurred, approximately 30% of metaplastic cells are eliminated during the resolution process. Thus, a safe approach to reducing IL-13-induced MCM would involve blocking mucous synthesis and storage, blocking secretion of stored mucus, and eliminating hyperplastic mucous cells. Understanding the molecular mechanisms of each of these processes is necessary for developing effective therapies for reducing mucous hypersecretion in asthma and leading to a repaired epithelium.
    Current Molecular Medicine 09/2008; 8(5):408-15. DOI:10.2174/156652408785160961 · 3.62 Impact Factor
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