Unique and overlapping gene expression patterns driven by IL-4 and IL-13 in the mouse lung

Lewis, Clayton S.; Aronow, Bruce J.; Hutton, John J.; Santeliz, Joanna; Dienger, Krista; Herman, Nancy; Finkelman, Fred D.; Wills‐Karp, Marsha

doi:10.1016/j.jaci.2009.01.003

Cited by 57 publications

(44 citation statements)

References 47 publications

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“…A number of mRNAs that were increased in Kras G12D ;Nkx2-1 +/-lungs overlapped with those induced in a HDM model of asthma (HDM-challenged mice; ref. 23), including ADAM8, AGR2, ALOX15, CHI3L4, IGF1, MUC5AC, MUC5B, RETNLA, and SAA3 ( Figure 6, highlighted in blue and green, and Supplemental Table 2), which supports the concept that some of the aspects of goblet cell differentiation are shared among these lung diseases. In order to identify genes regulated by NKX2-1 in the mucinous tumor model, mRNA analysis was performed in A549 human lung carcinoma cells, which bear a KRAS mutation and lack NKX2-1 expression ( Figure 5C).…”

Section: Nkx2-1 Inhibited Mutant Kras-induced Tumorigenesis In Vivosupporting

confidence: 63%

“…For analysis of genes regulated by NKX2-1 in A549 human lung carcinoma cells, mRNAs were isolated from lentiviral Nkx2-1-expressing and control A549 cells and subjected to mRNA microarray analysis (n = 3 per group). For analysis of genes induced in asthma, mRNAs were isolated from lungs of control and HDM-challenged mice and subjected to mRNA microarray analysis (n = 3 per group) (23). Several mRNAs associated with mucous genes -AGR2, MUC5AC, and MUC5B -were induced in both the mucinous tumor and the asthma mouse models and suppressed by NKX2-1 in A549 human lung carcinoma cells.…”

Section: Figurementioning

confidence: 99%

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KrasG12D and Nkx2-1 haploinsufficiency induce mucinous adenocarcinoma of the lung

Maeda

Tsuchiya

Hao³

et al. 2012

J. Clin. Invest.

138

198

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Mucinous adenocarcinoma of the lung is a subtype of highly invasive pulmonary tumors and is associated with decreased or absent expression of the transcription factor NK2 homeobox 1 (NKX2-1; also known as TTF-1). Here, we show that haploinsufficiency of Nkx2-1 in combination with oncogenic Kras G12D , but not with oncogenic EGFR L858R , caused pulmonary tumors in transgenic mice that were phenotypically similar to human mucinous adenocarcinomas. Gene expression patterns distinguished tumor goblet (mucous) cells from nontumorigenic airway and intestinal goblet cells. Expression of NKX2-1 inhibited urethane and oncogenic Kras G12D -induced tumorigenesis in vivo. Haploinsufficiency of Nkx2-1 enhanced Kras G12D -mediated tumor progression, but reduced EGFR L858R -mediated progression. Genome-wide analysis of gene expression demonstrated that a set of genes induced in mucinous tumors was shared with genes induced in a nontumorigenic chronic lung disease, while a distinct subset of genes was specific to mucinous tumors. ChIP with massively parallel DNA sequencing identified a direct association of NKX2-1 with the genes induced in mucinous tumors. NKX2-1 associated with the AP-1 binding element as well as the canonical NKX2-1 binding element. NKX2-1 inhibited both AP-1 activity and tumor colony formation in vitro. These data demonstrate that NKX2-1 functions in a context-dependent manner in lung tumorigenesis and inhibits Kras G12D -driven mucinous pulmonary adenocarcinoma. IntroductionMucinous adenocarcinoma of the lung (formerly known as mucinous bronchioalveolar cancer) is pathologically classified as tumor cells with goblet cell morphology containing abundant intracytoplasmic mucin (1). Invasive mucinous adenocarcinoma of the lung has a higher malignant potential than do the more common types of lung adenocarcinoma, such as acinar or papillary adenocarcinoma. Mucinous adenocarcinoma of the lung is associated with decreased or absent expression of the transcription factor NK2 homeobox 1 (NKX2-1; also known as TTF-1) and the expression of mucins, including mucin 5AC, oligomeric mucus/gel-forming (MUC5AC). Genetically, approximately 76% of mucinous adenocarcinomas of the lung have KRAS mutations, a frequent mutation in lung adenocarcinoma associated with tobacco use (2), but mucinous adenocarcinoma of the lung is rarely associated with EGFR mutations. In contrast, nonmucinous lung adenocarcinoma is frequently associated with EGFR mutations (∼45%), but less frequently with KRAS mutations (∼13%; ref. 1).NKX2-1 plays a critical role in lung morphogenesis and respiratory epithelial-specific gene expression, including activation of surfactant proteins and repression of mucins (3, 4). The potential oncogenic role of NKX2-1 in the pathogenesis of adenocarcinoma of the lung was proposed by findings that a region of 14q13.3 containing NKX2-1, NKX2-8, and PAX9 was amplified in approximately 10% of human lung adenocarcinoma (5-7). Loss-offunction and gain-of-function studies in human lung carcinoma and transformed cells supporte...

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Section: Nkx2-1 Inhibited Mutant Kras-induced Tumorigenesis In Vivosupporting

confidence: 63%

Section: Figurementioning

confidence: 99%

KrasG12D and Nkx2-1 haploinsufficiency induce mucinous adenocarcinoma of the lung

Maeda

Tsuchiya

Hao³

et al. 2012

J. Clin. Invest.

138

198

View full text Add to dashboard Cite

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“…FcεRIγ-deficient BMCMCs were not detectably respon- sive to IgE+Ag challenge, with or without IFN-γ ( Figure 2). The ability of IFN-γ to enhance dose-dependently the IgE+Ag-induced mast cell production of IL-13 is of particular interest (Supplemental Figure 2), since IL-13 is thought to contribute to the development of asthma through such effects as promoting subepithelial fibrosis (in part by upregulating synthesis of arginase-1), increasing mucus secretion, and eliciting AHR (35).…”

Section: Ifn-γ and Ifn-γr Contribute To This Model Of Chronic Allergimentioning

confidence: 99%

Identification of an IFN-γ/mast cell axis in a mouse model of chronic asthma

Yu¹,

Eckart²,

Morgan³

et al. 2011

J. Clin. Invest.

116

108

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Asthma is considered a Th2 cell-associated disorder. Despite this, both the Th1 cell-associated cytokine IFN-γ and airway neutrophilia have been implicated in severe asthma. To investigate the relative contributions of different immune system components to the pathogenesis of asthma, we previously developed a model that exhibits several features of severe asthma in humans, including airway neutrophilia and increased lung IFN-γ. In the present studies, we tested the hypothesis that IFN-γ regulates mast cell function in our model of chronic asthma. Engraftment of mast cell-deficient Kit W-sh/W-sh mice, which develop markedly attenuated features of disease, with wild-type mast cells restored disease pathology in this model of chronic asthma. However, disease pathology was not fully restored by engraftment with either IFN-γ receptor 1-null (Ifngr1 -/-) or Fcε receptor 1γ-null (Fcer1g -/-) mast cells. Additional analysis, including gene array studies, showed that mast cell expression of IFN-γR contributed to the development of many FcεRIγ-dependent and some FcεRIγ-independent features of disease in our model, including airway hyperresponsiveness, neutrophilic and eosinophilic inflammation, airway remodeling, and lung expression of several cytokines, chemokines, and markers of an alternatively activated macrophage response. These findings identify a previously unsuspected IFN-γ/mast cell axis in the pathology of chronic allergic inflammation of the airways in mice.

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“…Th2 CD4 + T cells are central to the pathogenesis of asthma through the cytokines they produce and are responsible for driving eosinophilia, goblet cell hyperplasia, airway hyperresponsiveness, and B cell isotype switching to IgE (15)(16)(17)(18)(19). Lung-resident dendritic cells (DCs) play a critical role in asthma by orchestrating the priming and polarization of CD4 + T cells (20)(21)(22)(23).…”

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confidence: 99%

GM-CSF–Licensed CD11b+ Lung Dendritic Cells Orchestrate Th2 Immunity to Blomia tropicalis

Zhou

Schlitzer

et al. 2014

The Journal of Immunology

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The Blomia tropicalis dust mite is prevalent in tropical and subtropical regions of the world. Although it is a leading cause of asthma, little is known how it induces allergy. Using a novel murine asthma model induced by intranasal exposure to B. tropicalis, we observed that a single intranasal sensitization to B. tropicalis extract induces strong Th2 priming in the lung draining lymph node. Resident CD11b+ dendritic cells (DCs) preferentially transport Ag from the lung to the draining lymph node and are crucial for the initiation of Th2 CD4+ T cell responses. As a consequence, mice selectively deficient in CD11b+ DCs exhibited attenuated Th2 responses and more importantly did not develop any allergic inflammation. Conversely, mice deficient in CD103+ DCs and CCR2-dependent monocyte-derived DCs exhibited similar allergic inflammation compared with their wild-type counterparts. We also show that CD11b+ DCs constitutively express higher levels of GM-CSF receptor compared with CD103+ DCs and are thus selectively licensed by lung epithelial-derived GM-CSF to induce Th2 immunity. Taken together, our study identifies GM-CSF–licensed CD11b+ lung DCs as a key component for induction of Th2 responses and represents a potential target for therapeutic intervention in allergy.

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Unique and overlapping gene expression patterns driven by IL-4 and IL-13 in the mouse lung

Cited by 57 publications

References 47 publications

KrasG12D and Nkx2-1 haploinsufficiency induce mucinous adenocarcinoma of the lung

KrasG12D and Nkx2-1 haploinsufficiency induce mucinous adenocarcinoma of the lung

Identification of an IFN-γ/mast cell axis in a mouse model of chronic asthma

GM-CSF–Licensed CD11b+ Lung Dendritic Cells Orchestrate Th2 Immunity to Blomia tropicalis

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