Protective role of retinoic acid from antiproliferative action of TNF-α on lung epithelial cells

Besnard, Valérie; Nabeyrat, Elodie; Henrion‐Caude, Alexandra; Chadelat, Katarina; Périn, Laurence; Bouc, Yves Le; Clément, Annick

doi:10.1152/ajplung.00368.2001

Cited by 29 publications

(20 citation statements)

References 37 publications

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“…The effect of RA is seen in the binding proteins both in lung tissue and in the culture medium of O 2 -exposed lungs. The effect of RA on culture 225 medium content of IGFBP-2 seen in our study was also seen in type II epithelial cell line cultures (21). It is possible that IGFBP-2 acts through a mechanism involving a competition for IGF-1 and IGF-1 receptor, although the affinity of IGFBP-2 for binding IGF-1 is less than that of IGFBP-3.…”

Section: Discussionsupporting

confidence: 66%

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Modulation of IGF-Binding Protein-2 and -3 in Hyperoxic Injury in Developing Rat Lung

et al. 2005

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Retinoids play an important role in lung development and repair. We showed that retinoic acid (RA) inhibits O 2 -induced fibroblast proliferation in rat lung explants. IGF-1, which enhances the proliferation of human fetal lung fibroblasts and stimulates collagen production during lung injury, has an important role in the lung injury/repair process. Interactions of IGF-1 with its receptor are modulated by IGF-binding proteins IGFBPs. We hypothesized that RA alters IGFBP-2 and -3 in hyperoxiaexposed neonatal lung and alters collagen production. Neonatal rat lungs were cultured in room air or 95% O 2 and 5% CO 2 for 3 d with or without RA. IGFBP-2 and -3 were measured both in culture medium and in lung tissue. Type I collagen and procollagen propeptide were analyzed in the lung tissue. Hyperoxia induced an increase in type I collagen that was significantly inhibited in the presence of RA. IGFBP-2 and IGFBP-3 in the lungs were decreased in hyperoxia but significantly increased in hyperoxia plus RA. In the culture medium, IGFBP-2 and -3 were not increased with hyperoxia but significantly increased in the presence of RA plus hyperoxia. There was no increase in IG-FBP-3 RNA transcript after RA treatment in either room air or O 2 exposure. In conclusion, RA modulates the secreted IGFBP-2 and -3 during O 2 exposure and inhibits the increase in collagen that occurs during lung injury. We speculate that RA protects against O 2 -induced neonatal lung injury through modulation of the IGFBPs. Bronchopulmonary dysplasia (BPD) is the most common chronic pulmonary disease of premature infants who require prolonged ventilation and/or O 2 therapy, usually after the presence of respiratory distress syndrome (1). Airway hyperreactivity, which can persist for several years, is one of the long-term sequelae of BPD. Improved perinatal and neonatal care, surfactant therapy, and new ventilation modalities have had a modest impact on the incidence of BPD in very small neonates, indicating a need for greater understanding of the mechanisms that lead to BPD.Histologic features of infants who die of BPD include chronic airway inflammation and squamous metaplasia of epithelial cells in airways (2). These changes are observed in animal models of hyperoxic damage to developing lung. For example, neonatal rats that are exposed to high O 2 concentrations develop alveolar epithelial thickening as well as an increased thickness of smooth muscle (3) and interstitial matrix, with abundant myofibroblasts (4). The increase in myofibroblasts in lung tissue correlates with increased type III collagen synthesis and fibrosis (5).A recent study of biopsy and autopsy material from lungs of infants who had BPD and had received both antenatal steroids and surfactant treatment showed developmental arrest, enlarged airspaces with minimal alveolarization and variable alveolar wall cellularity, and fibrosis (6). BPD in very low birth weight infants may result from inflammatory mediators' interfering with the signaling molecules in late lung development (7). Overe...

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Section: Discussionsupporting

confidence: 66%

“…In type II cell growth arrest, IGFBP-2 competes with IGF-1 receptor for IGF-1 (21). It also acts through IGF-dependent and IGFindependent mechanisms.…”

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confidence: 99%

Modulation of IGF-Binding Protein-2 and -3 in Hyperoxic Injury in Developing Rat Lung

et al. 2005

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“…It acts through a family of nuclear transcription factors known as retinoid receptors (Marill et al, 2003). While the principal effects of RA on target cells are inhibition of proliferation and induction of differentiation (Maden, 2002), it has also been shown that RA exhibits immunomodulatory and anti-inflammatory activities in various cell types (Mathew and Sharma, 2000;Besnard et al, 2002). For example, RA induces TNF-␣ mRNA destabilization in an RXR dependent manner in the rat hepatic macrophages (Motomura et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Retinoic acid inhibits expression of TNF-? and iNOS in activated rat microglia

Dheen

Yan

Zhou

et al. 2005

Glia

186

138

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The release of proinflammatory mediators such as tumor necrosis factor-alpha (TNF-alpha) and nitric oxide by microglia has been implicated in neurotoxicity in chronic neurodegenerative diseases such as Alzheimer's disease. As all-trans-retinoic acid (RA) has been reported to exert anti-inflammatory actions in various cell types, we have examined its effects on the expression of TNF-alpha and inducible nitric oxide synthase (iNOS) in microglia activated by beta-amyloid peptide (Abeta) and lipopolysaccharide (LPS). Exposure of primary cultures of rat microglial cells to Abeta or LPS stimulated the mRNA expression level of TNF-alpha (6-116-fold) and iNOS (8-500-fold) significantly. RA acted in a dose-dependent manner (0.1-10 microM) by attenuating both TNF-alpha (29-97%) and iNOS (61-96%) mRNA expression in microglia exposed to Abeta or LPS. RA-induced inhibition of TNF-alpha and iNOS mRNA expression in activated microglia was accompanied by the concomitant reduction in release of iNOS and TNF-alpha proteins as revealed by nitrite assay and ELISA, respectively. The anti-inflammatory effects of RA were correlated with the enhanced expression of retinoic acid receptor-beta, and transforming growth factor-beta1 as well as the inhibition of NF-kappaB translocation. These results suggest that RA may inhibit the neurotoxic effect of activated microglia by suppressing the production of inflammatory cytokines and cytotoxic molecules.

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“…[29][30][31] We were therefore interested in determining whether this cytokine could be a mediator of the observed effects of anti-CD9 mAbs on colon carcinoma cell morphology and proliferation. For this purpose, we first assessed whether exogenous TNF-a was able to induce changes in the morphology and inhibition of proliferation similar to those caused by anti-CD9 mAbs.…”

Section: Tnf-a Is Involved In Morphological Changes and In Inhibitionmentioning

confidence: 99%

The tetraspanin CD9 inhibits the proliferation and tumorigenicity of human colon carcinoma cells

Ovalle

Gutiérrez-López

Olmo

et al. 2007

Intl Journal of Cancer

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The implication of the tetraspanin CD9 in cancer has received much recent attention and an inverse correlation between CD9 expression and the metastatic potential and cancer survival rate has been established for different tumor types. In contrast to the well-established role of CD9 in metastasis, very little is known about the involvement of this tetraspanin in the process of development of primary tumors. In the present study, we present evidence on the implication of CD9 in colon carcinoma tumorigenesis. We report here that ectopic expression of CD9 in colon carcinoma cells results in enhanced integrin-dependent adhesion and inhibition of cell growth. Consistently with these effects, treatment of these cells with anti-CD9-specific antibodies resulted in (i) increased b1 integrin-mediated cell adhesion through a mechanism involving clustering of integrin molecules rather than altered affinity; (ii) induction of morphological changes characterized by the acquisition of an elongated cell phenotype; (iii) inhibition of cell proliferation with no significant effect on cell survival; (iv) increased expression of membrane TNF-a, and finally (v) inhibition of the in vivo tumorigenic capacity in nude mice. In addition, through the use of selective blockers of TNF-a, we have demonstrated that this cytokine partly mediates the antiproliferative effects of CD9. These results clearly establish for the first time a role for CD9 in the tumorigenic process. ' 2007 Wiley-Liss, Inc.Key words: CD9; TNF-a; proliferation; tumorigenicity; tetraspanin The tetraspanin CD9 is a widely distributed surface molecule implicated in diverse functions, including cell signaling, growth, adhesion and motility, metastasis and sperm-egg fusion. Like other members of the tetraspanin protein family, CD9 participates in the organization of cell surface protein microdomains, termed ''the tetraspanin web,'' through association with other transmembrane proteins including members of the integrin family of adhesion receptors. [1][2][3] The implication of CD9 in cancer has received much attention. An inverse correlation between its expression in primary tumors and the metastatic potential and patient survival rate has been established for melanomas and colon, lung and breast carcinomas. 1,4-8 The involvement of this tetraspanin in tumor progression has been inferred from the effects of CD9 antibodies or CD9 overexpression on tumor cell motility and migration. In this regard, it has been shown that overexpression of this tetraspanin in melanoma and breast, lung, pancreas and colon carcinoma cells suppresses the motility and metastatic potential of these cells. 5,7,9,10 mAbs directed to the CD9 molecule have also been shown to inhibit the migration of different types of carcinoma tumor cells and the transendothelial migration of melanoma cells. 11-13 Therefore, the inverse correlation observed between CD9 expression and the metastatic potential could be explained, at least in part, by the effects mediated by CD9 on cell adhesion and migration through the ...

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Protective role of retinoic acid from antiproliferative action of TNF-α on lung epithelial cells

Cited by 29 publications

References 37 publications

Modulation of IGF-Binding Protein-2 and -3 in Hyperoxic Injury in Developing Rat Lung

Modulation of IGF-Binding Protein-2 and -3 in Hyperoxic Injury in Developing Rat Lung

Retinoic acid inhibits expression of TNF-? and iNOS in activated rat microglia

The tetraspanin CD9 inhibits the proliferation and tumorigenicity of human colon carcinoma cells

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