Transgenic mice rich in endogenous omega-3 fatty acids are protected from colitis.
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-kappaB activity and expression of TNFalpha, inducible NO synthase, and IL-1beta, 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.
Hudert
Christian A
CA
Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Weylandt
Karsten H
KH
Lu
Yan
Y
Wang
Jingdong
J
Hong
Song
S
Dignass
Axel
A
Serhan
Charles N
CN
Kang
Jing X
JX
D000818:Animals; D003092:Colitis / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control*; D015232:Dinoprostone / Q000378:metabolism; D015777:Eicosanoids / Q000378:metabolism; D015525:Fatty Acids, Omega-3 / Q000378:metabolism*; D007249:Inflammation / Q000517:prevention & control; D007975:Leukotriene B4 / Q000378:metabolism; D008055:Lipids / Q000737:chemistry; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008956:Models, Chemical; D016328:NF-kappa B / Q000378:metabolism; D014466:Ultraviolet Rays
D015777:Eicosanoids; D015525:Fatty Acids, Omega-3; D008055:Lipids; D016328:NF-kappa B; D007975:Leukotriene B4; D015232:Dinoprostone