Abrogation of Bronchial Eosinophilic Inflammation and Airway Hyperreactivity in Signal Transducers and Activators of Transcription (STAT)6-deficient Mice

Akimoto, Toshihiko; Numata, Fumio; Tamura, Mina; Takata, Yoshimi; Higashida, Noriko; Takashi, Tohru; Takeda, Kiyoshi; Akira, Shizuo

doi:10.1084/jem.187.9.1537

Cited by 282 publications

(201 citation statements)

References 40 publications

(53 reference statements)

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“…Physiological studies demonstrate an inhibition of pulmonary eosinophil infiltration, mucus overproduction and AHR elicited by OVA challenge in mice harboring the STAT6 À/À null allele. 6,15 Expression profiling of the lung tissue of STAT-6 deficient following multiple dose mIL-13 lung instillation did not reveal any genes that met the dual fold change and statistical criteria. Specifically, none of the IL-13 modulated genes in wild-type Balb/C mice were statistically different (Po0.05) from vehicle in the absence of STAT6 function.…”

Section: Resultsmentioning

confidence: 98%

Gene expression analysis in a murine model of allergic asthma reveals overlapping disease and therapy dependent pathways in the lung

Follettie¹,

Ellis²,

Donaldson

et al. 2006

Pharmacogenomics J

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Accumulating evidence in animal models and human asthma support a central role for IL-13 signaling in disease pathogenesis. In order to identify asthma and therapy associated genes, global transcriptional changes were monitored in mouse lung following antigen challenge (ovalbumin (OVA)), either alone or in the presence of a soluble IL-13 antagonist. Changes in whole lung gene expression after instillation of mIL-13 were also measured both in wild type and STAT6 deficient mice. A striking overlap in the gene expression profiles induced by either OVA challenge or mIL-13 was observed, further strengthening the relationship of IL-13 signaling to asthma. Consistent with results from functional studies, a subset of the OVA-induced gene expression was significantly inhibited by a soluble IL-13 antagonist while IL-13-modulated gene expression was completely attenuated in the absence of STAT6-mediated signaling. Results from these experiments greatly expand our understanding of asthma and provide novel molecular targets for therapy and potential biomarkers of IL-13 antagonism.

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Section: Resultsmentioning

confidence: 98%

Gene expression analysis in a murine model of allergic asthma reveals overlapping disease and therapy dependent pathways in the lung

Follettie¹,

Ellis²,

Donaldson

et al. 2006

Pharmacogenomics J

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“…However, because the response was induced via a STAT6 pathway, an overall Th2-type environment may be initiated during the RSV response (24,26). STAT6 pathways are involved in allergen-induced airway hyperreactivity and mucus production (53,54). It is likely that multiple factors contribute to the pathophysiology during airway disease, including the genetic background and the cytokine profiles that are generated locally.…”

Section: Discussionmentioning

confidence: 99%

IL-13-Induced Airway Hyperreactivity During Respiratory Syncytial Virus Infection Is STAT6 Dependent

Tekkanat

Maassab

Cho

et al. 2001

The Journal of Immunology

130

109

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Airway damage and hyperreactivity induced during respiratory syncytial virus (RSV) infection can have a prolonged effect in infants and young children. These infections can alter the long-term function of the lung and may lead to severe asthma-like responses. In these studies, the role of IL-13 in inducing and maintaining a prolonged airway hyperreactivity response was examined using a mouse model of primary RSV infection. Using this model, there was evidence of significant airway epithelial cell damage and sloughing, along with mucus production. The airway hyperreactivity response was significantly increased by 8 days postinfection, peaked during days 10–12, and began to resolve by day 14. When the local production of Th1- and Th2-associated cytokines was examined, there was a significant increase, primarily in IL-13, as the viral response progressed. Treatment of RSV-infected mice with anti-IL-13 substantially inhibited airway hyperreactivity. Anti-IL-4 treatment had no effect on the RSV-induced responses. Interestingly, when IL-13 was neutralized, an early increase in IL-12 production was observed within the lungs, as was a significantly lower level of viral Ags, suggesting that IL-13 may be regulating an important antiviral pathway. The examination of RSV-induced airway hyperreactivity in STAT6−/− mice demonstrated a significant attenuation of the response, similar to the anti-IL-13 treatment. In addition, STAT6−/− mice had a significant alteration of mucus-producing cells in the airway. Altogether, these studies suggest that a primary factor leading to chronic RSV-induced airway dysfunction may be the inappropriate production of IL-13.

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“…In mouse models of allergic lung inflammation (41)(42)(43), contact hypersensitivity (44), and allergic diarrhea (45), STAT6 deficiency was accompanied by a lack of eosinophil influx into the sites of allergic inflammation. This effect may be at least partially due to defective eotaxin-1 production in these animals.…”

Section: Discussionmentioning

confidence: 99%

STAT6 Mediates Eotaxin-1 Expression in IL-4 or TNF-α-Induced Fibroblasts

Hoeck

Woisetschläger

2001

The Journal of Immunology

127

137

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Eosinophils are attracted to sites of allergic inflammation by a number of chemoattractants including eotaxin-1. This chemokine can be secreted from epithelial cells and fibroblasts after IL-4 and TNF-α stimulation in a synergistic fashion. TNF-α activated gene expression at the transcriptional level in a STAT6-dependent manner, because: 1) eotaxin-1 promoter luciferase constructs were TNF-α inducible in STAT6-defective HEK293 cells only on cotransfection of STAT6 expression vector, an effect that was partially mediated by activation-induced binding of NF-κB proteins to a composite STAT6/NF-κB element; 2) reporter constructs defective in STAT6 DNA binding did not respond to TNF-α stimulation; 3) eotaxin-1 protein secretion was detected only in STAT6-transfected HEK293 cell supernatants on TNF-α treatment; and 4) a trans-dominant negative STAT6 protein inhibited TNF-α-induced eotaxin-1 secretion in primary fibroblasts. TNF-α inducibility of the IL-8 and monocyte chemoattractant protein-1 genes was not dependent on STAT6 expression in the same experimental systems. The inducing effect of IL-4 and IL-13 was also mediated by STAT6. The synergistic effect of IL-4 and TNF-α observed at the RNA and the protein level was not seen at the promoter level. The data demonstrate that both IL-4 and TNF-α induce eotaxin-1 expression at the level of transcription via a STAT6-mediated pathway.

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Abrogation of Bronchial Eosinophilic Inflammation and Airway Hyperreactivity in Signal Transducers and Activators of Transcription (STAT)6-deficient Mice

Cited by 282 publications

References 40 publications

Gene expression analysis in a murine model of allergic asthma reveals overlapping disease and therapy dependent pathways in the lung

Gene expression analysis in a murine model of allergic asthma reveals overlapping disease and therapy dependent pathways in the lung

IL-13-Induced Airway Hyperreactivity During Respiratory Syncytial Virus Infection Is STAT6 Dependent

STAT6 Mediates Eotaxin-1 Expression in IL-4 or TNF-α-Induced Fibroblasts

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