Transgenic mice rich in endogenous omega-3 fatty acids are protected from colitis - PubMed (original) (raw)

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

Christian A Hudert et al. Proc Natl Acad Sci U S A. 2006.

Abstract

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.

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Conflict of interest statement

Conflict of interest statement: No conflicts declared.

Figures

Fig. 1.

Fig. 1.

Differential fatty acid profiles in WT and fat-1 transgenic mice. Whereas high levels of n-6 fatty acids characterize WT samples (A), n-3 fatty acids are nearly absent. In contrast, an abundance of EPA (20:5 n-3), docosapentaenoic acid (22:5 n-3), and DHA (22:6 n-3) can be found in fat-1 transgenic mice (B). The n-3 PUFA are marked with asterisks.

Fig. 2.

Fig. 2.

Colon inflammation activity in WT and fat-1 transgenic mice. (A) Macroscopic view (Upper) and microscopic hematoxylin and eosin staining (Lower) of the distal colon in WT control mice (Left), DSS-treated WT nontransgenic littermates (Center), and fat-1 mice (Right). (B) Colon shortening as a hallmark of DSS-induced colonic damage is reduced in fat-1 mice. ∗, P < 0.01 versus WT DSS-treated animals. (C) Histopathological scores for colonic inflammatory infiltration and epithelial damage in WT and fat-1 mice. ∗, P < 0.01 versus WT DSS. (D) Body weight change from 100% baseline over 8 days in fat-1 mice and WT littermates (n = 6 for each group), 5 days of DSS treatment and 3 days of normal drinking water. ∗, P < 0.05 versus WT DSS; ∗∗, P < 0.01 versus WT DSS. Mice were killed on day 8 (arrow), and samples were taken for further analysis.

Fig. 3.

Fig. 3.

LC–UV–tandem MS profiles of n-3 PUFA-derived lipid mediators. (A) DHA-derived resolvins and protectins (main pathway products identified were RvD3 and PD1/NPD1). (B) EPA-derived bioactive lipid mediators (identified mediators include RvE1, PGE3, and LTB5). (C) Arachidonic acid-derived bioactive mediators [PGE2, LTB4, and 15-hydroxyeicosatetraenoic acid (15-HETE) as precursor for the n-6 PUFA-derived lipoxin A4 (LXA4)]. (D) Presence of different lipid mediators in colon samples of fat-1 transgenic mice (n = 6) and WT animals (n = 6). ∗∗, P < 0.01; ∗, P < 0.05. Note the different scale for 15-HETE and PGE2 (on the right).

Fig. 4.

Fig. 4.

Markers of inflammation and mucoprotection. (A) NF-κB activation reflected in p65 ELISA activity shows significant differences in control baselines and in disease between WT and fat-1 mice. ∗, P < 0.05 versus WT DSS; ∗∗, P < 0.05 versus WT control. (B_–_F) Semiquantitative real-time PCR analysis of mRNA expression levels of inflammatory mediators TNFα, inducible NO synthase (iNOS), and IL-1β (B_–_D) and mucoprotective factors Tollip and TFF3 (E and F) in colons from WT and fat-1 mice after DSS exposure and fat-1 control mice, normalized as fold increase to the baseline of WT controls (dashed line). ∗, P < 0.05 versus WT DSS; ∗∗, P < 0.01 versus WT DSS. (G) ZO-1 expression profile. Compared with WT mice without treatment (Left), ZO-1 expression is down-regulated on the luminal epithelial surface in WT mice on day 4 (Center), whereas luminal continuity of expression is sustained in fat-1 mice (Right).

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