Anti-inflammatory and anti-angiogenic effect of long chain n-3 polyunsaturated fatty acids in intestinal microvascular endothelium

Appareil Digestif Environnement Nutrition (ADEN EA 4311), Medicine, University of Rouen, I.F.R. 23, Institute of Biomedical Research, 22 boulevard Gambetta, 76183 Rouen cedex, France.
Clinical nutrition (Edinburgh, Scotland) (Impact Factor: 4.48). 05/2011; 30(5):678-87. DOI: 10.1016/j.clnu.2011.05.002
Source: PubMed


The role of endothelial cells in inflammatory bowel disease has been recently emphasized. Endothelial activation and expression of adhesion molecules are critical for leukocytes recruitment into the inflammatory wall. Compelling evidence demonstrated anti-inflammatory effects of long chain n-3 PUFA in inflammatory models. We previously showed that long chain n-3 PUFA (EPA and DHA) inhibited inflammatory response in epithelial and dendritic cells. As long chain n-3 PUFA treatment led to a decreased expression of adhesion molecules in endothelial cells from other organs, we have now investigated their effect on intestinal endothelial cells in vitro and in colitic rats.
In vitro study: Primary culture of human intestinal microvascular endothelial cells (HIMEC) were pre-treated with DHA and then incubated with IL-1β. In vivo study: Colitis was induced in 2 groups at day0 by intrarectal injection of 2-4-6-trinitrobenzen sulfonic acid (TNBS). Rats received by gavage either fish oil, rich in EPA and DHA (TNBS+n-3) or an isocaloric isolipidic oil formula for 14 days.
DHA led to a decreased VCAM-1, TLR4, cyclooxygenase-2 and VEGFR2 expression and a decreased production of IL-6, IL-8 and GM-CSF and a reduced production of PGE(2) and LTB(4) (p < 0.001) in IL-1β-induced HIMEC. Similarly, dietary intervention with fish oil rich in EPA and DHA significantly decreased colon production of PGE(2) and LTB(4,) endothelial VCAM-1 and VEGFR2 in rats with colitis.
Data obtained from in vitro and in vivo studies reveal a potential anti-angiogenic role of long chain n-3 PUFA in intestinal endothelial cells. This protective effect of long chain n-3 PUFA may partly explain the observed benefit of dietary intake of long chain n-3 PUFA in IBD development.

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Available from: Nabile Boukhettala, Apr 07, 2014
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    • "Breynaert et al. also described a colonic gene profile associated with both inflammation and fibrosis. COX-2 is a marker which for decades has clearly been associated with acute inflammation [25], [26], [27], [28] but which also increases significantly with time in fibrosis models, pulmonary fibrosis [29] and colonic fibrosis included [30]. In our observation a similar relationship between COX-2 and MR parameters linked both fibrosis and inflammation. "
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    ABSTRACT: Background Magnetic resonance colonography (MRC) has been developed to assess inflammatory bowel diseases. We aimed to assess the feasibility of MRC in rats with TNBS-induced chronic colitis and to confront imaging results with fibrosis and stenosing features of the model. Materials and Methods Chronic colitis was induced in 12 rats by weekly intra-rectal injection of increasing doses of TNBS for 6 weeks, while 8 control rats received the vehicle. At week 7, MRC was performed. Fibrosis scores were assessed and fibrosis mediators measured. Results Chronic colitis was associated with significant body weight loss (p<0.0001) and higher colon weight/length compared to controls (p = 0.0004). Fibrosis mediators and histological scores were significantly higher in rats with TNBS than in controls: α-SMA expression (0.9 versus 0.61, p = 0.0311) and fibrosis score (p = 0.0308). Colon wall thickness was higher in rats with TNBS than in controls: maximal thickness (2.38 versus 0.74 mm, p<0.0001) and minimal thickness (1.33 versus 0.48 mm, p<0.0001). Wall signal intensity on T2w images was higher in rats with TNBS than in controls (9040 versus 6192, p = 0.0101) and correlated with fibrosis score (r = 0.5214; p = 0.04). Luminal narrowing was higher in rats with TNBS (50.08 versus 10.33%, p<0.0001) and correlated with α-SMA expression (r = 0.5618; p = 0.01). Stenosis was observed in 7/9 rats with TNBS and in no controls (p = 0.0053). Conclusions MRC is feasible and easily distinguishes rats with colitis from controls. MRC signs correlated with fibrosis parameters. MRC evaluation may be part of a new anti-fibrosis drug assessment in experimental models of chronic colitis.
    Full-text · Article · Jul 2014 · PLoS ONE
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    • "Interestingly, the authors suggested the existence of a relationship between the anticancer effect of ω-3 PUFAs and their anti-inflammatory effect, since they observed an increased expression of the immunosuppressive factor TGF-β and a decreased expression of the pro-inflammatory and pro-angiogenic chemokine IL-8 in the colonic mucosa of DHM-treated rats fed with a FO-enriched diet. This result is in agreement with previous findings indicating that ω-3 PUFAs inhibit neo-angiogenesis in animal models of inflamed mucosa and colon cancer [113, 114], and with the observed ω-3 PUFA-induced inhibition of IL-8 production in IL-1β-stimulated endothelial cells (HUVEC) [113] or in UVB- or TNF-α-stimulated HaCaT keratinocytes [115]. Moreover, as it is known that both IL-8 and TGF-β are among the cytokines secreted at high levels and specifically by the M2 monocytic phenotype [116], this finding suggests that ω-3 PUFAs may exert direct influence on the polarization of M1/M2 monocytic cells in the context of tumor microenvironment. "
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    ABSTRACT: A large body of evidence has emerged over the past years to show the critical role played by inflammation in the pathogenesis of several diseases including some cardiovascular, neoplastic, and neurodegenerative diseases, previously not considered inflammation-related. The anti-inflammatory action of ω-3 polyunsaturated fatty acids (PUFAs), as well as their potential healthy effects against the development and progression of the same diseases, has been widely studied by our and others' laboratories. As a result, a rethinking is taking place on the possible mechanisms underlying the beneficial effects of ω-3 PUFAs against these disorders, and, in particular, on the influence that they may exert on the molecular pathways involved in inflammatory process, including the production of inflammatory cytokines and lipid mediators active in the resolving phase of inflammation. In the present review we will summarize and discuss the current knowledge regarding the modulating effects of ω-3 PUFAs on the production of inflammatory cytokines and proresolving or protective lipid mediators in the context of inflammatory, metabolic, neurodegenerative, and neoplastic diseases.
    Full-text · Article · Apr 2013
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    • "OA was also found to have some anti-inflammatory effect to some extent but not comparable to EPA and DHA. These anti-inflammatory effects are in accordance with the previous studies on different cells such as RAW264.7 [13,41], THP-1 [11], HIMEC [10] and animal models [42,43]. In murine 3T3-L1 adipocytes it has been also shown that EPA and DHA are able to reduce MCP-1 expression and NFkB translocation [33]. "
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    ABSTRACT: Background On the basis that high fat diet induces inflammation in adipose tissue, we wanted to test the effect of dietary saturated and polysunsaturated fatty acids on human adipose tissue and adipocytes inflammation. Moreover we wanted to determine if TLR2 and TLR4 are involved in this pathway. Methods Human adipose tissue and adipocytes primary cultures were treated with endotoxin-free BSA conjugated with SFA (lauric acid and palmitic acid - LA and PA) and PUFA (eicosapentaeneic acid, docosahexaenoic acid and oleic acid - EPA, DHA and OA) with or without LPS. Cytokines were then assayed by ELISA (TNF-alpha, IL-6 and MCP-1). In order to determine if TLR2 and TLR4 are activated by fatty acid (FA), we used HEK-Blue cells transfected by genes from TLR2 or TLR4 pathways associated with secreted alkaline phosphatase reporter gene. Results None of the FA tested in HEK-Blue cells were able to activate TLR2 or TLR4, which is concordant with the fact that after FA treatment, adipose tissue and adipocytes cytokines levels remain the same as controls. However, all the PUFA tested: DHA, EPA and to a lesser extent OA down-regulated TNF-alpha, IL-6 and MCP-1 secretion in human adipose tissue and adipocytes cultures. Conclusions This study first confirms that FA do not activate TLR2 and TLR4. Moreover by using endotoxin-free BSA, both SFA and PUFA tested were not proinflammatory in human adipose tissue and adipocytes model. More interestingly we showed that some PUFA exert an anti-inflammatory action in human adipose tissue and adipocytes model. These results are important since they clarify the relationship between dietary fatty acids and inflammation linked to obesity.
    Full-text · Article · Dec 2012 · Lipids in Health and Disease
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