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

doi:10.1073/pnas.0601280103

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

*Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
^†Department of Gastroenterology, Charité University Medicine, Virchow Campus, 13353 Berlin, Germany; and
^§Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115

Edited by Charles A. Dinarello, University of Colorado Health Sciences Center, Denver, CO, and approved June 9, 2006
↵ ^‡C.A.H. and K.H.W. contributed equally to this work. (received for review February 15, 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-κB activity and expression of TNFα, inducible NO synthase, and IL-1β, 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.

Footnotes

^¶To whom correspondence should be addressed at:
Massachusetts General Hospital, 149 13th Street, Room 4433, Charlestown, MA 02129.
E-mail: jxkang{at}partners.org
Author contributions: C.A.H., K.H.W., A.D., and J.X.K. designed research; C.A.H., Y.L., J.W., and S.H. performed research; Y.L., S.H., and C.N.S. contributed new reagents/analytic tools; C.A.H., K.H.W., Y.L., and J.X.K. analyzed data; and C.A.H., K.H.W., C.N.S., and J.X.K. wrote the paper.
Conflict of interest statement: No conflicts declared.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

Abbreviations:

n-3,

omega-3;

n-6,

omega-6;

PUFA,

polyunsaturated fatty acids;

EPA,

eicosapentaenoic acid;

DHA,

docosahexaenoic acid;

IBD,

inflammatory bowel disease;

RvE1,

resolvin E1;

RvD3,

resolvin D3;

NPD1,

neuroprotectin D1;

PD1,

protectin D1;

LTB4,

leukotriene B4;

LTB5,

leukotriene B5;

PGE3,

prostaglandin E3;

PGE2,

prostaglandin E2;

TFF3,

trefoil factor 3;

Tollip,

Toll-interacting protein;

ZO-1,

zonula occludens-1;

DSS,

dextran sodium sulfate.