Rôle de la protéine CFTR sur le métabolisme de l'acide arachidonique et l'expression de la phospholipase A2 secrétée de type IIA dans les cellules épithéliales pulmonaires

PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Impact of CFTR ΔF508 mutation on prostaglandin E 2 production and type IIA phospholipase A 2 expression by pulmonary epithelial cells

International audienceCystic fibrosis (CF) is characterized by an exacerbated inflammatory pulmonary response with excessive production of inflammatory mediators. We investigated here the impact of cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction on prostaglandin E2 (PGE2) production and type IIA secreted phospholipase A2 (sPLA2-IIA) expression. We show that both resting and LPS-stimulated human respiratory epithelial cell line bearing DeltaF508 mutation on CFTR (CF cells) released more PGE2 than control cell line. This was accompanied by enhanced expression and activity of cyclooxygenase-2 in CF cells. PGE2 release was attenuated after experimentally induced retrafficking of the DeltaF508-CFTR at the plasma membrane. sPLA2-IIA expression occurred at higher levels in CF cells than in control cells and was enhanced by LPS and PGE2. Suppression of PGE2 synthesis by aspirin led to an inhibition of LPS-induced sPLA2-IIA expression. Higher activation of NF-kappaB was observed in CF cells compared with control cells and was enhanced by LPS. However, addition of PGE2 or aspirin had no effect on NF-kappaB activation. LPS-induced sPLA2-IIA expression was reduced by an NF-kappaB inhibitor. We suggest that the lack of the CFTR in the plasma membrane results in a PGE2 overproduction and an enhanced sPLA2-IIA expression. This expression is upregulated by NF-kappaB and amplified by PGE2 via a unidentified signaling pathway

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doi:10.1073/pnas.0605200103 This information is current as of March 2007. High-resolution figures, a citation map, links to PubMed and Google Scholar, etc., can be found at: www.pnas.org/cgi/content/full/103/33/12487 This article cites 34 articles, 21 of which you can access for free at: www.pnas.org/cgi/content/full/103/33/12487#BIBL This article has been cited by other articles: www.pnas.org/cgi/content/full/103/33/12487#otherarticles Receive free email alerts when new articles cite this article- sign up in the box at the top right corner of the article or click here. To reproduce this article in part (figures, tables) or in entirety, see: www.pnas.org/misc/rightperm.shtml To order reprints, see: www.pnas.org/misc/reprints.shtml Involvement of Toll-like receptor 5 in the recognition of flagellated bacteri

Surfactant Protein-A and Phosphatidylglycerol Suppress Type IIA Phospholipase A2 Synthesis via Nuclear Factor-κB

International audienceWe previously showed that surfactant inhibits the synthesis of type IIA secretory phospholipase A2 (sPLA2-IIA) by alveolar macrophages. These cells have been identified as the main source of this enzyme in an animal model of acute lung injury. The aim of the present study was to identify the surfactant components involved in the inhibition of sPLA2-IIA expression in alveolar macrophages and the signaling pathways that mediate this inhibition. Our results show that various surfactant preparations can inhibit sPLA2-IIA expression in endotoxin-stimulated alveolar macrophages. Both the surfactant protein (SP)-A and the surfactant phospholipid fraction inhibit this expression. The surfactant phospholipid dioleylphosphatidylglycerol (DOPG) abolishes sPLA2-IIA expression, whereas dipalmitoylphosphatidylcholine does not. Chromatographic analysis and confocal microscopy revealed that phosphatidylglycerol was rapidly incorporated and metabolized by alveolar macrophages and that its metabolites accumulate in the cytosol. Nuclear factor-kappaB (NF-kappaB) modulates sPLA2-IIA expression in endotoxin-activated alveolar macrophages, and surfactant preparations, surfactant phospholipid fraction, SP-A, and DOPG indeed suppressed NF-kappaB activation. In summary, our results show that SP-A and DOPG play a role in the surfactant-mediated inhibition of sPLA2-IIA expression in alveolar macrophages and that this inhibition occurs via a downregulation of NF-kappaB activation

Familial partial lipodystrophy type 2 and obesity, two adipose tissue pathologies with different inflammatory profiles

International audienceThe transition to metabolically unhealthy obesity (MUO) is driven by the limited expandability of adipose tissue (AT). Familial Partial Lipodystrophy type 2 (FPLD2) is an alternative model for AT dysfunction that is suitable for comparison with obesity. While MUO is associated with low-grade systemic inflammation, studies of inflammation in FPLD2 have yielded inconsistent results. Consequently, comparison of inflammation markers between FPLD2 and obesity is of great interest to better understand the pathophysiological defects of FPLD2. Objective: To compare the levels of inflammatory biomarkers between a population of patients with FPLD2 due to the same ‘Reunionese’ LMNA variant and a population of patients with obesity (OB group). Methods: Adiponectin, leptin, IL-6, TNF-α and MCP-1 plasma levels were measured by enzyme-linked immuno assays for 60 subjects with FPLD2 and for 60 subjects with obesity. The populations were closely matched for age, sex, and diabetic status. Results: Metabolic outcomes were similar between the two populations. Adiponectinemia and leptinemia were lower in the FPLD2 group than in the OB group (p < 0.01 for both), while MCP-1 levels were higher in the FPLD2 than in the OB group (p < 0.01). Levels of other inflammatory markers were not significantly different. Conclusions: Insulin-resistant patients with FPLD2 and obesity share common complications related to AT dysfunction. Inflammatory biomarker analyses demonstrated that MCP-1 levels and adiponectin levels differ between patients with FPLD2 and patients with obesity. These two AT pathologies thus appear to have different inflammatory profiles