Tumor necrosis factor‐α and embryonic mouse lung morphogenesis

Jaskoll, Tina; Boyer, Paul D.; Melnick, Michael

doi:10.1002/aja.1002010205

Cited by 30 publications

(20 citation statements)

References 65 publications

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“…The impact of TNF-alpha on lung branching morphogenesis has not been studied in detail. Early reports suggested that TNF-alpha enhanced embryonic lung branching morphogenesis (Jaskoll et al, 1994). However, numerous studies in both human and animal models have shown a correlation between TNF-alpha and inhibition of lung growth and development.…”

Section: Discussionmentioning

confidence: 98%

TNF-alpha represses transcription of human Bone Morphogenetic Protein-4 in lung epithelial cells

Zhu

Huang

et al. 2007

Gene

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Bone Morphogenetic Proteins are key signaling molecules in vertebrate development. Little is known about Bmp gene regulation in any organ. In Drosophila, the Bmp gene, dpp is regulated by Dorsal, the invertebrate homologue of Rel-NF-kB. In this study we examined whether TNF-alpha, which activates NF-kB, can regulate Bmp4 gene expression. TNF-alpha reduced Bmp4 mRNA in lung adenocarcinoma A549 cells and repressed transcriptional activity of the human Bmp4 promoter in a dose-dependent manner. Similar repression was observed when the Bmp4 promoter was co-transfected with a p65 (RelA) expression vector in the absence of TNF-alpha treatment, suggesting that RelA mediates the effect of TNF-alpha. In support of this finding, the repressor effect of TNF-alpha on Bmp4 was abrogated by a co-transfected dominant negative mutant of IkB (S32A/S36A). The human Bmp4 promoter contains 3 putative consensus binding sites for NF-kB. Surprisingly, only one of the latter binding sites was capable of binding NF-kB. Repressor effect of NF-kB was not dependent on any of the three binding sites, but localized to a 122 bp fragment which bound both RelA and SP1. SP1 stimulated transcription, whereas increasing doses of RelA opposed this effect. In vivo, TNF-alpha inhibited branching morphogenesis and LacZ gene expression in Bmp4-lacz transgenic lungs. These data support a model in which TNF-alpha-induced RelA interacts with SP1 to bring about transcriptional repression of Bmp4 gene. These findings provide a mechanistic paradigm for interactions between mediators of inflammation and morphogenesis with relevant implications for normal lung development and pathogenesis of disease.

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Section: Discussionmentioning

confidence: 98%

TNF-alpha represses transcription of human Bone Morphogenetic Protein-4 in lung epithelial cells

Zhu

Huang

et al. 2007

Gene

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“…We have previously demonstrated that TNF is important to embryonic pulmonary branching morphogenesis (Jaskoll et al, 1994a;Melnick et al, 1996). Thus, we in- vestigated the spatiotemporal distribution of TNF and its two receptors, TNF-R1 and TNF-R2, in the embryonic SMGs.…”

Section: Tnf Il-6 and Cognate Receptorsmentioning

confidence: 99%

“…Given that TGF-␤s have been shown to be an important regulator of embryonic salivary gland morphogenesis in vitro and in vivo (Hardman et al, 1994;Jaskoll et al, 1994a) and that both TGF-␤2 and TGF-␤3 null mice exhibit abnormal lungs (Kaartinen et al, 1995;Sanford et al, 1997), we postulated that TGF-␤2 and/or TGF-␤3 are essential for normal in vivo embryonic salivary gland development. Thus, we evaluated perinatal and neonatal TGF-␤2 and TGF-␤3 null mice.…”

Section: Tgf-␤2 and Tgf-␤3 Null Micementioning

confidence: 99%

“…Almost certainly, the cellular conversation occurs not only between epithelium and mesenchyme, but within these tissues as well. Such conversations in other branching organs are typically mediated by hormones, growth factors, cytokines, and the like in such a way as to translate endocrine, autocrine, and paracrine signals into specific gene responses regulating cell division, apoptosis, and histodifferentiation (Jaskoll et al, 1994a(Jaskoll et al, , 1996Melnick et al, 1996;Miettinen et al, 1997;Zhao et al, 1998). Relatively little is known about this in SMGs.…”

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confidence: 99%

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Submandibular gland morphogenesis: Stage-specific expression of TGF-?/EGF, IGF, TGF-?, TNF, and IL-6 signal transduction in normal embryonic mice and the phenotypic effects of TGF-?2, TGF-?3, and EGF-r null mutations

1999

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Branching morphogenesis of the mouse submandibular gland (SMG) is dependent on cell-cell conversations between and within epithelium and mesenchyme. Such conversations are typically mediated in other branching organs (lung, mammary glands, etc.) by hormones, growth factors, cytokines, and the like in such a way as to translate endocrine, autocrine, and paracrine signals into specific gene responses regulating cell division, apoptosis, and histodifferentiation. We report here the protein expression in embryonic SMGs of four signal transduction pathways: TGF-␣/EGF/EGF-R; IGF-II/IGF-IR/IGF-IIR; TGF-␤s and cognate receptors; TNF, IL-6, and cognate receptors. Their in vivo spatiotemporal expression is correlated with specific stages of progressive SMG development and particular patterns of cell proliferation, apoptosis, and mucin expression. Functional necessity regarding several of these pathways was assessed in mice with relevant null mutations (TGF-␤2, TGF-␤ 3 , EGF-R). Among many observations, the following seem of particular importance: (1) TGF-␣ and EGF-R, but not EGF, are found in the Initial and Pseudoglandular Stages of SMG development; (2) ductal and presumptive acini lumena formation was associated with apoptosis and TNF/TNF-R1 signalling; (3) TGF-␤2 and TGF-␤3 null mice have normal SMG phenotypes, suggesting the presence of other pathways of mitostasis; (4) EGF-R null mice displayed an abnormal SMG phenotype consisting of decreased branching. These and other findings provide insight into the design of future functional studies. Anat Rec 256: 252-268, 1999. 1999 Wiley-Liss, Inc.

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“…Organ cultures of embryonic lung rudiments have been used by many investigators to examine control factors involved in lung branching morphogenesis. A number of substances, such as epidermal growth factor, transforming growth factor-,Bl (TGF-,B1), tumor necrosis factor-a, glucocorticoids, platelet derived growth factor, and retinoic acid, have been tested for their effects on lung branching morphogenesis (17)(18)(19)(20)(21)(22)(23)(24)(25)(26). These and other studies illustrate the complexity of lung branching morphogenesis, which may involve growth factors, components of extracellular matrix, matrix-degrading enzymes, and cell-surface molecules (27)(28)(29)(30)(31)(32)(33).…”

mentioning

confidence: 99%

Keratinocyte growth factor and embryonic rat lung morphogenesis.

Shiratori¹,

Oshika²,

Ung³

et al. 1996

Am J Respir Cell Mol Biol

106

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We examined possible roles of keratinocyte growth factor (KGF) and hepatocyte growth factor (HGF) in lung morphogenesis. By polymerase chain reaction, transcripts for both KGF and its receptor were detected early (rat gestational days 16 and 14, respectively) and their abundance increased during lung morphogenesis. To evaluate possible role of KGF in lung morphogenesis, day 14 lung explants were cultured in Dulbecco's modified Eagle medium + 10% fetal calf serum for 1 to 4 days in the presence (5-50 ng/ml) or absence of KGF (control). KGF (at 25 and 50 ng/ml) induced a marked reduction in the number of terminal branches and destination of the distal epithelium into cyst-like structures. These effects of exogenous KGF were progressively diminished by increasing concentrations of anti-KGF (2-16 micrograms/ml). Electron microscopic examination revealed that the epithelial cells of the cystic structures contained lamellar bodies, and were therefore type II cells and/or their progenitors. Northern blot analysis showed higher expression of surfactant protein C (SP-C) mRNA (a marker for alveolar epithelial type II cells) in KGF-treated fetal lungs. In situ hybridization of the KGF-treated lungs revealed that the SP-C mRNA-expressing cells were arranged distally in the form of linear arrays, a pattern distinctly different from that in control lungs. Acidic fibroblast growth factor, which also binds KGF receptors, in the presence of heparin mimicked the effect of KGF on branching. Transforming growth factor-beta(1) (TGF-beta 1) inhibited branching of fetal lungs in culture, and this effect dominated over that induced by KGF. Blocking of endogenous HGF with antibodies or addition of HGF to cultures of fetal lung explants had no significant effect on branching or growth. In conclusion, KGF markedly influences branching, and epithelial growth, differentiation, and patterning during lung morphogenesis.

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Tumor necrosis factor‐α and embryonic mouse lung morphogenesis

Cited by 30 publications

References 65 publications

TNF-alpha represses transcription of human Bone Morphogenetic Protein-4 in lung epithelial cells

TNF-alpha represses transcription of human Bone Morphogenetic Protein-4 in lung epithelial cells

Submandibular gland morphogenesis: Stage-specific expression of TGF-?/EGF, IGF, TGF-?, TNF, and IL-6 signal transduction in normal embryonic mice and the phenotypic effects of TGF-?2, TGF-?3, and EGF-r null mutations

Keratinocyte growth factor and embryonic rat lung morphogenesis.

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