IL-1β Disrupts Postnatal Lung Morphogenesis in the Mouse

Bry, Kristina; Whitsett, Jeffrey A.; Lappalainen, Urpo

doi:10.1165/rcmb.2006-0116oc

Cited by 163 publications

(148 citation statements)

References 69 publications

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“…Although these effects may reflect an important role of Tle1 in the development of these organs, the inflammatory state caused by constitutive activation of NF-κB and expression of inflammatory cytokines and chemokines could be responsible for many of these findings. This concept is supported by prior work from several groups that found inflammation in mice can lead to delayed pigmentation (39), alveolar hypoplasia, and poor postnatal growth and decreased survival (28,40).…”

Section: Discussionmentioning

confidence: 55%

Tle1 tumor suppressor negatively regulates inflammation in vivo and modulates NF-κB inflammatory pathway

Ramasamy

Sáez

Mukhopadhyay

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Tle1 (transducin-like enhancer of split 1) is a corepressor that interacts with a variety of DNA-binding transcription factors and has been implicated in many cellular functions; however, physiological studies are limited. Tle1-deficient (Tle1 Δ/Δ ) mice, although grossly normal at birth, exhibit skin defects, lung hypoplasia, severe runting, poor body condition, and early mortality. Tle1 Δ/Δ mice display a chronic inflammatory phenotype with increased expression of inflammatory cytokines and chemokines in the skin, lung, and intestine and increased circulatory IL-6 and G-CSF, along with a hematopoietic shift toward granulocyte macrophage progenitor and myeloid cells. Tle1 Δ/Δ macrophages produce increased inflammatory cytokines in response to Toll-like receptor (TLR) agonists and lipopolysaccharides (LPS), and Tle1 Δ/Δ mice display an enhanced inflammatory response to ear skin 12-O-tetradecanoylphorbol-13-acetate treatment. Loss of Tle1 not only results in increased phosphorylation and activation of proinflammatory NF-κB but also results in decreased Hes1 (hairy and enhancer of split-1), a negative regulator of inflammation in macrophages. Furthermore, Tle1 Δ/Δ mice exhibit accelerated growth of B6-F10 melanoma xenografts. Our work provides the first in vivo evidence, to our knowledge, that TLE1 is a major counterregulator of inflammation with potential roles in a variety of inflammatory diseases and in cancer progression.T ransducin-like enhancer of split 1 (TLE1) belongs to a family of corepressor proteins called transducin-like enhancer of split, or TLEs. Groucho, the TLE homolog in Drosophila, has crucial roles in neurogenesis, segmentation, and sex determination (1). These corepressors do not bind directly to DNA but rather interact with many different classes of transcription factors and help create a repressor complex (1, 2).Vertebrates express five different TLEs (TLE1-4, AES), although the distinct functions of each of the TLEs has not been well determined. TLE1, the most studied among the Groucho family proteins in mammalian systems, is widely expressed in different tissues and cell types and has been implicated in neuronal differentiation (3, 4) and pancreatic beta cell development (5). TLE1 has tumor suppressor activity (6-8) as well as oncogenic functions in cancer (9, 10). TLE1 associates with many important transcription factors integral for cell proliferation and differentiation, including Runx2 to block rRNA expression (11), HES1 to suppresses MASH2 expression (12), and TCF/LEF proteins to block Wnt target gene activation (13). TLE1 also represses NF-κB activity (14,15). Involvement in these diverse cellular functions and diseases was studied primarily in vitro or using in vivo overexpression systems. The major physiological function of TLE1, however, remains poorly understood.A few recent studies suggest TLE1 might regulate immune function. For example, a single noncoding nucleotide polymorphism within the TLE1 locus was associated with inflammatory bowel diseases (16), and in human monocytes,...

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Section: Discussionmentioning

confidence: 55%

Tle1 tumor suppressor negatively regulates inflammation in vivo and modulates NF-κB inflammatory pathway

Ramasamy

Sáez

Mukhopadhyay

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Relevant to this point, transgenic expression of Il1b in the mouse airway epithelium during the saccular stage has been shown to alter lung development. 52 As NF-kB drives the transcription of multiple pro-inflammatory genes, the cumulative effects of these factors may explain why lung abnormalities in our model are more severe than with conditional Il1b expression alone; however, the findings from this study supports the idea that the saccular stage is particularly vulnerable to the effects of epithelial-derived inflammation.…”

Section: Epithelial Nf-kb and Lung Developmentmentioning

confidence: 52%

Epithelial-Derived Inflammation Disrupts Elastin Assembly and Alters Saccular Stage Lung Development

Benjamin

Meer

et al. 2016

The American Journal of Pathology

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The highly orchestrated interactions between the epithelium and mesenchyme required for normal lung development can be disrupted by perinatal inflammation in preterm infants, although the mechanisms are incompletely understood. We used transgenic (inhibitory kB kinase b transactivated) mice that conditionally express an activator of the NF-kB pathway in airway epithelium to investigate the impact of epithelial-derived inflammation during lung development. Epithelial NF-kB activation selectively impaired saccular stage lung development, with a phenotype comprising rapidly progressive distal airspace dilation, impaired gas exchange, and perinatal lethality. Epithelial-derived inflammation resulted in disrupted elastic fiber organization and down-regulation of elastin assembly components, including fibulins 4 and 5, lysyl oxidase likee1, and fibrillin-1. Fibulin-5 expression by saccular stage lung fibroblasts was consistently inhibited by treatment with bronchoalveolar lavage fluid from inhibitory kB kinase b transactivated mice, Escherichia coli lipopolysaccharide, or tracheal aspirates from preterm infants exposed to chorioamnionitis. Expression of a dominant NF-kB inhibitor in fibroblasts restored fibulin-5 expression after lipopolysaccharide treatment, whereas reconstitution of fibulin-5 rescued extracellular elastin assembly by saccular stage lung fibroblasts. Elastin organization was disrupted in saccular stage lungs of preterm infants exposed to systemic inflammation. Our study reveals a critical window for elastin assembly during the saccular stage that is disrupted by inflammatory signaling and could be amenable to interventions that restore elastic fiber assembly in the developing lung.

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“…After overnight fixation at 4°C, the tissue was dehydrated and paraffin embedded, cut into 5-m sections, stained with hemotoxylin and eosin, and examined with light microscopy. 15,16 We performed radial alveolar counts, as previously described. 17 From the center of the respiratory bronchiole, a perpendicular line is drawn to the edge of the acinus, and the number of the septa intersected by that line are counted.…”

Section: Histologymentioning

confidence: 99%

MicroRNA Expression Profile in Hyperoxia-Exposed Newborn Mice During the Development of Bronchopulmonary Dysplasia

et al. 2011

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BACKGROUND: Bronchopulmonary dysplasia (BPD) is a chronic lung disease of preterm neonates; the underlying pathogenesis is not fully understood. MicroRNAs (length 21-25 nucleotides) are ribonucleic acid (RNA) molecules that have important functions in development, cellular differentiation, apoptosis, proliferation, and migration; very little is known regarding their role in developmental lung diseases. METHODS: We exposed neonatal mice to either room air or 60% oxygen, beginning at birth, and we used microRNA microarray and real-time polymerase chain reaction on lung samples. RESULTS: The hyperoxia-exposed mice developed a lung injury that mimicked human BPD. Fifty-one microRNAs shared similar profiles in the hyperoxia-exposed BPD lungs and the normal lungs, which indicates that those microRNAs might play a protective role during the septation process. In the BPD lungs, compared to the control lungs, 14 microRNAs were up-regulated, and 7 microRNAs were down-regulated, which indicates that these microRNAs might play an important role in the development of BPD. Some of the candidate microRNAs can regulate cell proliferation. CONCLUSIONS: To our knowledge, this study is the first to identify microRNAs associated with BPD development, which provides a clue for further investigation of their function in BPD development.

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IL-1β Disrupts Postnatal Lung Morphogenesis in the Mouse

Cited by 163 publications

References 69 publications

Tle1 tumor suppressor negatively regulates inflammation in vivo and modulates NF-κB inflammatory pathway

Tle1 tumor suppressor negatively regulates inflammation in vivo and modulates NF-κB inflammatory pathway

Epithelial-Derived Inflammation Disrupts Elastin Assembly and Alters Saccular Stage Lung Development

MicroRNA Expression Profile in Hyperoxia-Exposed Newborn Mice During the Development of Bronchopulmonary Dysplasia

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