Predominant pathogenic role of tumor necrosis factor in experimental colitis in mice

360

278

Omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acids (PUFA) are the precursors of potent lipid mediators and play an important role in regulation of inflammation. Generally, n-6 PUFA promote inflammation whereas n-3 PUFA have antiinflammatory properties, traditionally attributed to their ability to inhibit the formation of n-6 PUFA-derived proinflammatory eicosanoids. Newly discovered resolvins and protectins are potent antiinflammatory lipid mediators derived directly from n-3 PUFA with distinct pathways of action. However, the role of the n-3 PUFA tissue status in the formation of these antiinflammatory mediators has not been addressed. Here we show that an increased n-3 PUFA tissue status in transgenic mice that endogenously biosynthesize n-3 PUFA from n-6 PUFA leads to significant formation of antiinflammatory resolvins and effective reduction in inflammation and tissue injury in colitis. The endogenous increase in n-3 PUFA and related products did not decrease n-6 PUFA-derived lipid mediators such as leukotriene B4 and prostaglandin E2. The observed inflammation protection might result from decreased NF-B activity and expression of TNF␣, inducible NO synthase, and IL-1␤, with enhanced mucoprotection probably because of the higher expression of trefoil factor 3, Toll-interacting protein, and zonula occludens-1. These results thus establish the fat-1 transgenic mouse as a new experimental model for the study of n-3 PUFA-derived lipid mediators. They add insight into the molecular mechanisms of inflammation protection afforded by n-3 PUFA through formation of resolvins and protectins other than inhibition of n-6 PUFA-derived eicosanoid formation.inflammation ͉ inflammatory bowel disease ͉ lipid mediators ͉ resolvins ͉ protectins

Section: Expression Of Genes Involved In Inflammation and Colitis Patmentioning

confidence: 67%

Transgenic mice rich in endogenous omega-3 fatty acids are protected from colitis

Hudert

Weylandt

Lü

et al. 2006

360

278

“…For example, the overexpression of TNF-␣ in mice results in the development of a Crohn's disease-like phenotype. Also, TNF-␣ deficient mice as well as anti-TNF-␣ treatment reduces intestinal inf lammation in several animal models (21). More importantly, blockade of TNF-␣ is now a widely used therapeutic strategy in the management of Crohn's disease and rheumatoid arthritis (22).…”

Section: Discussionmentioning

confidence: 99%

Resolvin E1, an endogenous lipid mediator derived from omega-3 eicosapentaenoic acid, protects against 2,4,6-trinitrobenzene sulfonic acid-induced colitis

Arita

Yoshida

Hong

et al. 2005

538

437

Resolvin E1 (RvE1; 5S,12R,18R-trihydroxyeicosapentaenoic acid) is an antiinflammatory lipid mediator derived from omega-3 fatty acid eicosapentaenoic acid (EPA). At the local site of inflammation, aspirin treatment enhances EPA conversion to 18R-oxygenated products, including RvE1, which carry potent antiinflammatory signals. Here, we obtained evidence for reduced leukocyte infiltration in a mouse peritonitis model, where the administration of EPA and aspirin initiated the generation of RvE1 in the exudates. Similar results were obtained with the administration of synthetic RvE1, which blocked leukocyte infiltration. RvE1 also protected against the development of 2,4,6-trinitrobenzene sulfonic acidinduced colitis. The beneficial effect was reflected by increased survival rates, sustained body weight, improvement of histologic scores, reduced serum anti-2,4,6-trinitrobenzene sulfonic acid IgG, decreased leukocyte infiltration, and proinflammatory gene expression, including IL-12 p40, TNF-␣, and inducible nitric oxide synthase. Thus, the endogenous lipid mediator RvE1 counterregulates leukocyte-mediated tissue injury and proinflammatory gene expression. These findings show an endogenous mechanism that may underlie the beneficial actions of omega-3 EPA and provide targeted approaches for the treatment of intestinal inflammation.antiinflammation ͉ aspirin-triggered lipid mediators ͉ omega-3 PUFA ͉ resolvins

“…In fact, in some models, TNF-␣ neutralization or deletion improves the severity of colitis (20,21), whereas in others, disease severity is actually increased (22). This discrepancy may be a reflection of the differences between the particular animal model studied and the human condition.…”

Section: Discussionmentioning

confidence: 99%

TNF-αneutralization ameliorates the severity of murine Crohn's-like ileitis by abrogation of intestinal epithelial cell apoptosis

Marini

Bamias

Rivera–Nieves

et al. 2003

183

138

Tumor necrosis factor ␣ (TNF-␣) is an important mediator of programmed cell death, and TNF-␣ blockade significantly improves disease severity in several inflammatory conditions, including Crohn's disease (CD), one of the idiopathic inflammatory bowel diseases. However, the precise mechanism(s) of action of anti-TNF-␣ therapy in CD remains poorly understood. SAMP1͞YitFc mice develop a spontaneous ileitis with similarities to human CD in regard to histological features as well as response to conventional treatments. In this report, we tested the novel hypothesis that the beneficial effects of anti-TNF-␣ therapy in CD are mediated by a mechanism that involves down-regulation of intestinal epithelial cell (IEC) apoptosis. Similar to the efficacy of monoclonal anti-TNF-␣ antibodies in human CD, a single injection of a chimeric anti-murine TNF-␣ antibody into SAMP1͞YitFc mice resulted in a marked suppression of intestinal inflammation and epithelial cell damage compared with mice injected with an isotype control antibody. These effects were associated with a significant reduction in apoptosis of freshly isolated IEC as assessed by propidium iodide staining and DNA laddering. In contrast, an increase in lamina propria mononuclear cell apoptosis was observed in anti-TNF-␣-treated mice compared with control. These results were confirmed in vivo by using the terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling-assay. In addition, neutralization of TNF-␣ reduced membrane bound FAS͞CD95 expression in IEC from SAMP1͞YitFc mice compared with control antibody. These data demonstrate a novel mechanism of action of anti-TNF-␣ therapy that involves homeostatic regulation of mucosal cell apoptosis, which results in the net decrease of chronic inflammation typically found in CD.