Transiting exoplanets from the CoRoT space mission. VIII. CoRoT-7b: the first super-Earth with measured radius

Copyright © The European Southern Observatory (ESO)Aims. We report the discovery of very shallow (ΔF/F ≈ 3.4×10−4), periodic dips in the light curve of an active V = 11.7 G9V star observed by the CoRoT satellite, which we interpret as caused by a transiting companion. We describe the 3-colour CoRoT data and complementary ground-based observations that support the planetary nature of the companion. Methods. We used CoRoT colours information, good angular resolution ground-based photometric observations in- and out- of transit, adaptive optics imaging, near-infrared spectroscopy, and preliminary results from radial velocity measurements, to test the diluted eclipsing binary scenarios. The parameters of the host star were derived from optical spectra, which were then combined with the CoRoT light curve to derive parameters of the companion. Results. We examined all conceivable cases of false positives carefully, and all the tests support the planetary hypothesis. Blends with separation >0.40'' or triple systems are almost excluded with a 8 × 10−4 risk left. We conclude that, inasmuch we have been exhaustive, we have discovered a planetary companion, named CoRoT-7b, for which we derive a period of 0.853 59 ± 3 × 10−5 day and a radius of Rp = 1.68 ± 0.09 REarth. Analysis of preliminary radial velocity data yields an upper limit of 21 MEarth for the companion mass, supporting the finding. Conclusions. CoRoT-7b is very likely the first Super-Earth with a measured radius. This object illustrates what will probably become a common situation with missions such as Kepler, namely the need to establish the planetary origin of transits in the absence of a firm radial velocity detection and mass measurement. The composition of CoRoT-7b remains loosely constrained without a precise mass. A very high surface temperature on its irradiated face, ≈1800–2600 K at the substellar point, and a very low one, ≈50 K, on its dark face assuming no atmosphere, have been derived

Comparaison de modèles in vitro de cellules épithéliales des voies respiratoires pour la sécrétion de mucus et le processus inflammatoire

Les maladies respiratoires chroniques telles que l’asthme, la BPCO ou encore la mucoviscidose sont une des principales causes de morbidité et de mortalité dans le monde. Elles sont responsables de la détérioration des voies respiratoires, et sont caractérisées par une inflammation persistante ainsi qu’un excès de mucus. L’exposition au tabac est un facteur de risque majeur, et participe à l’aggravation de ces maladies. L’exposition à la fumée de cigarette affecte le système immunitaire, augmente le risque d’infections bactériennes, et induit la synthèse de mucus. Aussi, l’excès de mucus au sein des voies aériennes altère l’efficacité thérapeutique des traitements administrables par voie inhalée, généralement utilisés lors de ces affections pulmonaires. La thérapie génique est porteuse d’espoir, et semble être un bon moyen pour traiter ces maladies localement et sur le long terme. Néanmoins, les vecteurs utilisés sont confrontés à l’épaisse barrière viscoélastique que forme le mucus. Notre étude s’est donc attachée à comparer plusieurs lignées épithéliales pulmonaires humaines afin de déterminer un modèle in vitro capable de produire du mucus et des cytokines inflammatoires. Ainsi, nous avons stimulé différentes lignées avec de l’extrait de fumée de cigarette (CSE) et / ou du LPS d’Escherichia coli à faible dose, et mesuré l’expression et la libération des cytokines et du mucus. Notre travail a pu mettre en évidence que la lignée NCI H292 semble la plus adéquate. Elle est la plus sensible à la production de mucus après stimulation pendant 24h avec du CSE à 4% associé au LPS à 0.1μg/mL. De plus, ses taux d’ARNm de MUC5AC et MUC5B augmentent en réponse à l’exposition au CSE+LPS. Enfin, l’utilisation du LPS chez NCI H292, permet d’induire une augmentation de la sécrétion de médiateurs inflammatoires. Ainsi, l’utilisation de ce modèle d’étude in vitro d’exposition des cellules NCI H292 au CSE+LPS va permettre de mesurer de façon stable et reproductible l’efficacité des vecteurs de thérapie génique sur une lignée épithéliale bronchique humaine

Comparaison de modèles in vitro de cellules épithéliales des voies respiratoires pour la sécrétion de mucus et le processus inflammatoire

Les maladies respiratoires chroniques telles que l’asthme, la BPCO ou encore la mucoviscidose sont une des principales causes de morbidité et de mortalité dans le monde. Elles sont responsables de la détérioration des voies respiratoires, et sont caractérisées par une inflammation persistante ainsi qu’un excès de mucus. L’exposition au tabac est un facteur de risque majeur, et participe à l’aggravation de ces maladies. L’exposition à la fumée de cigarette affecte le système immunitaire, augmente le risque d’infections bactériennes, et induit la synthèse de mucus. Aussi, l’excès de mucus au sein des voies aériennes altère l’efficacité thérapeutique des traitements administrables par voie inhalée, généralement utilisés lors de ces affections pulmonaires. La thérapie génique est porteuse d’espoir, et semble être un bon moyen pour traiter ces maladies localement et sur le long terme. Néanmoins, les vecteurs utilisés sont confrontés à l’épaisse barrière viscoélastique que forme le mucus. Notre étude s’est donc attachée à comparer plusieurs lignées épithéliales pulmonaires humaines afin de déterminer un modèle in vitro capable de produire du mucus et des cytokines inflammatoires. Ainsi, nous avons stimulé différentes lignées avec de l’extrait de fumée de cigarette (CSE) et / ou du LPS d’Escherichia coli à faible dose, et mesuré l’expression et la libération des cytokines et du mucus. Notre travail a pu mettre en évidence que la lignée NCI H292 semble la plus adéquate. Elle est la plus sensible à la production de mucus après stimulation pendant 24h avec du CSE à 4% associé au LPS à 0.1μg/mL. De plus, ses taux d’ARNm de MUC5AC et MUC5B augmentent en réponse à l’exposition au CSE+LPS. Enfin, l’utilisation du LPS chez NCI H292, permet d’induire une augmentation de la sécrétion de médiateurs inflammatoires. Ainsi, l’utilisation de ce modèle d’étude in vitro d’exposition des cellules NCI H292 au CSE+LPS va permettre de mesurer de façon stable et reproductible l’efficacité des vecteurs de thérapie génique sur une lignée épithéliale bronchique humaine

Characterization of the MMP/TIMP Imbalance and Collagen Production Induced by IL-1β or TNF-α Release from Human Hepatic Stellate Cells

International audienceInflammation has an important role in the development of liver fibrosis in general and the activation of hepatic stellate cells (HSCs) in particular. It is known that HSCs are themselves able to produce cytokines and chemokines, and that this production may be a key event in the initiation of fibrogenesis. However, the direct involvement of cytokines and chemokines in HSC (self-)activation remains uncertain. In this study, the effects of pro-inflammatory cytokines IL-1α and β, TNF-α, and IL-8 on the activation state of HSCs were examined, in comparison to the pro-fibrogenic mediator TGF-β1. LX-2 cells were stimulated for 24 or 48 hours with recombinant human form of the pro-inflammatory cytokines IL-1α and β, TNF-α, and IL-8, and also the pro-fibrogenic mediator TGF-β1. Two drugs were also evaluated, the anti-TNF-α monoclonal antibody infliximab and the IL-1 receptor antagonist anakinra, regarding their inhibitory effects. In LX-2 human HSC, treatment with TGF-β1 are associated with downregulation of the metalloproteinase (MMP)-1 and MMP-3, with upregulation of tissue inhibitor of metalloproteinase (TIMP)-1, collagen type I α1, collagen type IV α1, α-SMA, endothelin-1 and PDGF-BB. Cytokines and chemokines expression were found to be downregulated, excepting IL-6. In contrast, we observed that LX-2 exposure to IL-1, TNF-α and IL-8 can reverse the phenotype of pro-fibrogenic activated cells. Indeed, MMP-1, MMP-3 and MMP-9 were found elevated, associated with downregulation of α-SMA and/or PDGF-BB, and a greater expression of IL-1β, IL-6, IL-8, CXCL1 and CCL2. Lastly, we found that infliximab and anakinra successfully inhibits effects of TNF-α and IL-1 respectively in LX-2 cells. Infliximab and anakinra may be of value in preclinical trials in chronic liver disease. Overall, our results suggest that (i) pro-inflammatory mediators exert complex effects in HSCs via an MMP/TIMP imbalance, and (ii) targeting IL-1 signaling may be a potentially valuable therapeutic strategy in chronic liver disease

Influence of inflammasome pathway activation in macrophages on the matrix metalloproteinase expression of human hepatic stellate cells

International audienceInflammasomes are protein complexes that produce IL-1β in response to damage or pathogens. As such, inflammasomes are involved in several types of hepatic fibrosis. However, the mechanisms by which these complexes drive the liver's fibrogenic status remain unclear. We co-cultured differentiated macrophages (the THP-1 cell line or human monocyte-derived macrophages (MDMs)) with human hepatic fibroblasts (either the LX-2 cell line or primary human hepatic stellate cells (HSCs)). The inflammasome pathway was activated with lipopolysaccharide (LPS) and monosodium urate (MSU) crystals, and the HSCs' responses were analyzed. Our results show that co-culture of HSCs with THP-1 cells upregulated transcription of the genes coding for metalloproteinase (MMP)-3 and MMP-9. After inflammasome pathway activation, the HSCs' phenotype was the same in the presence of THP-1 cells or MDMs (i.e. upregulation of MMP-3, MMP-9, and the pro-inflammatory cytokine IL-1β). We found that two cytokines were involved in these changes IL-1β regulated MMP-3 and IL-1β mRNA expression, whereas TNF-α regulated MMP-9 mRNA expression. Experiments with primary cells revealed that a general inflammatory environment is responsible for the downregulation of pro-fibrotic markers. Our present results suggest that inflammasome pathway activation in macrophages leads to a pro-inflammatory environment for HSCs leading to MMP/TIMP imbalance and enhanced fibrolytic properties

Impact of JAK/STAT inhibitors on human monocyte-derived-macrophages stimulated by cigarette smoke extract and LPS

International audienceThe main risk factor for chronic obstructive pulmonary disease (COPD) is cigarette smoke (CS). It can alter many immune cells functions such as phagocytosis, efferocytosis and cytokine production. Cytokines play a role in the orchestration of inflammation in COPD. The JAK/STAT pathways are among the most important signaling components of cytokines. The objective of this work was to investigate the role of JAK/STAT pathway with regard to cytokine release and microsphere uptake capacity (to minimize the non-specific scavenging) in human monocyte-derived-macrophages (MDMs). MDMs were stimulated by cigarette smoke extract (CSE) alone or in combination with lipopolysaccharide (LPS). CSE alone was not associated with significant changes in the cytokine, with the exception of IL-8/CXCL8 production. However; CSE disturbed cytokine production in LPS-stimulated MDMs. CSE increase CXCL-8 and CCL2 release in LPS-stimulated MDM and suppressed the production of IL-6 and CXCL1 in these cells. CSE also decreased microsphere uptake capacity by MDMs. Then, CSE + LPS-stimulated MDMs were treated with two different JAK inhibitors. AG490 (specific inhibitor of JAK2) and ruxolitinib (inhibitor of JAK1 and JAK2). JAK/STAT inhibitors, particularly ruxolitinib, attenuated in cytokine production without completely inhibiting when compared with dexamethasone. On the other hand, the cells exposed to dexamethasone are nearly unable to capture the microspheres, while both JAK inhibitors does not affect the uptake capacity. In summary, our results showed the versatility of ruxolitinib which might bring a better balance disturbance of cytokine release and uptake capacity. The information regarding their distinctive effect, JAK/STAT inhibitors may be useful in the development of novel treatments for COPD

Characterization of human airway epithelial cell lines as in vitro models of chronic obstructive pulmonary disease

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Effects of the nerve growth factor and its carrier protein on the inflammatory response from human monocytes

International audienceBackground: The nerve growth factor (NGF) has been previously shown to be involved in cellular proliferation, differentiation, survival, or wound healing. This factor displays a variety of biological effects that yet remain to be explored. Previous data on cell lines show a pro-inflammatory role of NGF on monocytes.Objectives: The objective of the study was to investigate the pro-inflammatory effect of NGF, using a model of fresh human monocytes.Methods: Monocytes obtained from PBMC were exposed to NGF at various concentrations. Alternatively, monocytes were exposed to BSA, the NGF carrier protein without the NGF. Gene expression and cytokine release in the supernatant were monitored.Results: We found that NGF increased the expression of pro-inflammatory, chemotactic, and remodeling genes such as interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and C-X-C motif ligand (CXCL)8. The protein levels of CXCL8 and matrix metalloproteinase (MMP)-9 were also increased in the cell supernatants following NGF exposure. BSA alone was found to drive part of this response, bringing nuance to the inflammatory potential of the NGF.Conclusion: These data suggest that NGF is able to enhance monocyte inflammatory responses once cells are stimulated with another signal but is possibly not able to directly activate it. This could have implications for example in patients with bacterial infections, where NGF could worsen the local inflammation by over-activating immune cells

Effects of TGF-β1 treatment on the fibrolysis balance, fibrotic response and inflammatory response in LX-2 cells.

<p>The cells were treated with 3 ng/mL rhTGF-β1 for 24 hours or 48 hours. <b>(A)</b> mRNA expression levels of metalloproteinases (MMP-1, MMP-3, MMP-2, MMP-9) and tissue inhibitor of metalloproteinases (TIMP-1) were measured and normalized against that of GAPDH (using real-time PCR) after 24 hours of treatment. <b>(B)</b> mRNA expression of fibrogenesis factors (COL1A1/collagen I α1, COL4A1/collagen IV α1), myofibroblast differentiation factors (ACTA2/α-smooth muscle actin) and myofibroblast activation factors (EDN1/endothelin-1, PDGFB/platelet-derived growth factor-BB), as measured with real-time PCR and normalized against that of GAPDH after 24 hours of treatment. <b>(C)</b> mRNA expression of proinflammatory cytokines (IL1B/interleukin-1β, TNFA/tumor necrosis factor-α, IL6/interleukin-6) and chemokines (CXCL8/interleukin-8, CXCL1/GROα, CCL2/MCP1), as measured with real-time PCR and normalized against that of GAPDH after 24 hours of treatment. <b>(D)</b> IL-1β, TNF-α, IL-6 and IL-8 secretions into the supernatant by LX-2 cells were detected with an ELISA after 24 hours of treatment. <b>(E)</b> Pro-collagen I α1 secretion into the supernatant by LX-2 cells was detected with an ELISA after 48 hours of treatment. <b>(F)</b> Collagen type I α1 protein expression was determined by western blot of LX-2 cell lysates after 24 hours treatment and relative quantification was evaluated using densitometry. <b>(G)</b> Gelatinase activities of MMP-9 and MMP-2 released by LX-2 cells into the supernatant after 48 hours of treatment were evaluated by zymography and normalized densitometry. Results are expressed as the mean ± SEM of three independent experiments. * p<0.05, ** p<0.01, *** p<0.001, relative to a control.</p

Ethanol upregulates the P2X7 purinergic receptor in human macrophages

International audienceAlcohol consumption is considered to be the third leading cause of death in the United States. In addition to its direct toxicity, ethanol has two contrasting effects on the immune system the nucleotide oligomerization domain-like receptor pyrin domain-containing-3 (NLRP3) inflammasome is inhibited by acute ethanol exposure but activated by chronic ethanol exposure. Purinergic receptors (especially the P2X7 receptor) are able to activate the NLRP3 inflammasome, and are involved in many ethanol-related diseases (such as gout, pulmonary fibrosis, alcoholic steatohepatitis and certain cancers). We hypothesized that ethanol regulates purinergic receptors and thus modulates the NLRP3 inflammasome's activity. In experiments with monocyte-derived macrophages, we found that interleukin (IL)-1β secretion was inhibited after 7h of exposure (but not 48 h of exposure) to ethanol. The disappearance of ethanol's inhibitory effect on IL-1β secretion after 48 h was not mediated by the upregulated production of IL-1β, IL-1α, IL-6 or the inflammasome components NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain, and caspase 1. P2X7R expression was upregulated by ethanol, whereas expression of the P2X4 and P2X1 receptors was not. Taken as a whole, our results suggest that ethanol induces NLRP3 inflammasome activation by upregulating the P2X7 receptor. This observation might have revealed a new mechanism for inflammation in ethanol-related diseases