title: Endothelium-Derived 5-Methoxytryptophan Is a Circulating Anti-Inflammatory Molecule That Blocks Systemic Inflammation.
abstract: Systemic inflammation has emerged as a key pathophysiological process that induces multiorgan injury and causes serious human diseases. Endothelium is critical in maintaining cellular and inflammatory homeostasis, controlling systemic inflammation, and progression of inflammatory diseases. We postulated that endothelium produces and releases endogenous soluble factors to modulate inflammatory responses and protect against systemic inflammation.
  
  
  
  To identify endothelial cell-released soluble factors that protect against endothelial barrier dysfunction and systemic inflammation.
  
  
  
  We found that conditioned medium of endothelial cells inhibited cyclooxgenase-2 and interleukin-6 expression in macrophages stimulated with lipopolysaccharide. Analysis of conditioned medium extracts by liquid chromatography-mass spectrometry showed the presence of 5-methoxytryptophan (5-MTP), but not other related tryptophan metabolites. Furthermore, endothelial cell-derived 5-MTP suppressed lipopolysaccharide-induced inflammatory responses and signaling in macrophages and endotoxemic lung tissues. Lipopolysaccharide suppressed 5-MTP level in endothelial cell-conditioned medium and reduced serum 5-MTP level in the murine sepsis model. Intraperitoneal injection of 5-MTP restored serum 5-MTP accompanied by the inhibition of lipopolysaccharide-induced endothelial leakage and suppression of lipopolysaccharide- or cecal ligation and puncture-mediated proinflammatory mediators overexpression. 5-MTP administration rescued lungs from lipopolysaccharide-induced damages and prevented sepsis-related mortality. Importantly, compared with healthy subjects, serum 5-MTP level in septic patients was decreased by 65%, indicating an important clinical relevance.
  
  
  
  We conclude that 5-MTP belongs to a novel class of endothelium-derived protective molecules that defend against endothelial barrier dysfunction and excessive systemic inflammatory responses.
authors.affiliation: From the Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan (Y.-F.W., H.-F.W., G.-L.L., J.-Y.W., S.-F.Y., K.K.W., C.-C.K.); Institute of Molecular Medicine, National Tsing Hua University, Hsinchu, Taiwan (Y.-F.W.); Division of Nephrology (Y.-J.H.), Division of Infectious Diseases and Tropical Medicine (Y.-S.Y.), Department of Medicine, Tri-Service General Hospital (Y.-J.H., Y.-S.Y.), and Graduate Institutes of Life Sciences and Biochemistry (Y.-J.H., G.-L.L., Y.-S.Y., C.-C.K.), National Defense Medical Center, Taipei, Taiwan; Metabolomic Research Center, China Medical University Hospital (S.-F.Y., K.K.W., C.-C.K.) and Graduate Institute of Basic Medical Science (S.-F.Y., K.K.W., C.-C.K.), China Medical University, Taichung, Taiwan; and Department of Medicine, University of Texas, Houston (K.K.W.).
authors.forename: Yi-Fu
authors.initials: YF
authors.lastname: Wang
authors.affiliation: From the Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan (Y.-F.W., H.-F.W., G.-L.L., J.-Y.W., S.-F.Y., K.K.W., C.-C.K.); Institute of Molecular Medicine, National Tsing Hua University, Hsinchu, Taiwan (Y.-F.W.); Division of Nephrology (Y.-J.H.), Division of Infectious Diseases and Tropical Medicine (Y.-S.Y.), Department of Medicine, Tri-Service General Hospital (Y.-J.H., Y.-S.Y.), and Graduate Institutes of Life Sciences and Biochemistry (Y.-J.H., G.-L.L., Y.-S.Y., C.-C.K.), National Defense Medical Center, Taipei, Taiwan; Metabolomic Research Center, China Medical University Hospital (S.-F.Y., K.K.W., C.-C.K.) and Graduate Institute of Basic Medical Science (S.-F.Y., K.K.W., C.-C.K.), China Medical University, Taichung, Taiwan; and Department of Medicine, University of Texas, Houston (K.K.W.).
authors.forename: Yu-Juei
authors.initials: YJ
authors.lastname: Hsu
authors.affiliation: From the Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan (Y.-F.W., H.-F.W., G.-L.L., J.-Y.W., S.-F.Y., K.K.W., C.-C.K.); Institute of Molecular Medicine, National Tsing Hua University, Hsinchu, Taiwan (Y.-F.W.); Division of Nephrology (Y.-J.H.), Division of Infectious Diseases and Tropical Medicine (Y.-S.Y.), Department of Medicine, Tri-Service General Hospital (Y.-J.H., Y.-S.Y.), and Graduate Institutes of Life Sciences and Biochemistry (Y.-J.H., G.-L.L., Y.-S.Y., C.-C.K.), National Defense Medical Center, Taipei, Taiwan; Metabolomic Research Center, China Medical University Hospital (S.-F.Y., K.K.W., C.-C.K.) and Graduate Institute of Basic Medical Science (S.-F.Y., K.K.W., C.-C.K.), China Medical University, Taichung, Taiwan; and Department of Medicine, University of Texas, Houston (K.K.W.).
authors.forename: Hsu-Feng
authors.initials: HF
authors.lastname: Wu
authors.affiliation: From the Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan (Y.-F.W., H.-F.W., G.-L.L., J.-Y.W., S.-F.Y., K.K.W., C.-C.K.); Institute of Molecular Medicine, National Tsing Hua University, Hsinchu, Taiwan (Y.-F.W.); Division of Nephrology (Y.-J.H.), Division of Infectious Diseases and Tropical Medicine (Y.-S.Y.), Department of Medicine, Tri-Service General Hospital (Y.-J.H., Y.-S.Y.), and Graduate Institutes of Life Sciences and Biochemistry (Y.-J.H., G.-L.L., Y.-S.Y., C.-C.K.), National Defense Medical Center, Taipei, Taiwan; Metabolomic Research Center, China Medical University Hospital (S.-F.Y., K.K.W., C.-C.K.) and Graduate Institute of Basic Medical Science (S.-F.Y., K.K.W., C.-C.K.), China Medical University, Taichung, Taiwan; and Department of Medicine, University of Texas, Houston (K.K.W.).
authors.forename: Guan-Lin
authors.initials: GL
authors.lastname: Lee
authors.affiliation: From the Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan (Y.-F.W., H.-F.W., G.-L.L., J.-Y.W., S.-F.Y., K.K.W., C.-C.K.); Institute of Molecular Medicine, National Tsing Hua University, Hsinchu, Taiwan (Y.-F.W.); Division of Nephrology (Y.-J.H.), Division of Infectious Diseases and Tropical Medicine (Y.-S.Y.), Department of Medicine, Tri-Service General Hospital (Y.-J.H., Y.-S.Y.), and Graduate Institutes of Life Sciences and Biochemistry (Y.-J.H., G.-L.L., Y.-S.Y., C.-C.K.), National Defense Medical Center, Taipei, Taiwan; Metabolomic Research Center, China Medical University Hospital (S.-F.Y., K.K.W., C.-C.K.) and Graduate Institute of Basic Medical Science (S.-F.Y., K.K.W., C.-C.K.), China Medical University, Taichung, Taiwan; and Department of Medicine, University of Texas, Houston (K.K.W.).
authors.forename: Ya-Sung
authors.initials: YS
authors.lastname: Yang
authors.affiliation: From the Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan (Y.-F.W., H.-F.W., G.-L.L., J.-Y.W., S.-F.Y., K.K.W., C.-C.K.); Institute of Molecular Medicine, National Tsing Hua University, Hsinchu, Taiwan (Y.-F.W.); Division of Nephrology (Y.-J.H.), Division of Infectious Diseases and Tropical Medicine (Y.-S.Y.), Department of Medicine, Tri-Service General Hospital (Y.-J.H., Y.-S.Y.), and Graduate Institutes of Life Sciences and Biochemistry (Y.-J.H., G.-L.L., Y.-S.Y., C.-C.K.), National Defense Medical Center, Taipei, Taiwan; Metabolomic Research Center, China Medical University Hospital (S.-F.Y., K.K.W., C.-C.K.) and Graduate Institute of Basic Medical Science (S.-F.Y., K.K.W., C.-C.K.), China Medical University, Taichung, Taiwan; and Department of Medicine, University of Texas, Houston (K.K.W.).
authors.forename: Jing-Yiing
authors.initials: JY
authors.lastname: Wu
authors.affiliation: From the Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan (Y.-F.W., H.-F.W., G.-L.L., J.-Y.W., S.-F.Y., K.K.W., C.-C.K.); Institute of Molecular Medicine, National Tsing Hua University, Hsinchu, Taiwan (Y.-F.W.); Division of Nephrology (Y.-J.H.), Division of Infectious Diseases and Tropical Medicine (Y.-S.Y.), Department of Medicine, Tri-Service General Hospital (Y.-J.H., Y.-S.Y.), and Graduate Institutes of Life Sciences and Biochemistry (Y.-J.H., G.-L.L., Y.-S.Y., C.-C.K.), National Defense Medical Center, Taipei, Taiwan; Metabolomic Research Center, China Medical University Hospital (S.-F.Y., K.K.W., C.-C.K.) and Graduate Institute of Basic Medical Science (S.-F.Y., K.K.W., C.-C.K.), China Medical University, Taichung, Taiwan; and Department of Medicine, University of Texas, Houston (K.K.W.).
authors.forename: Shaw-Fang
authors.initials: SF
authors.lastname: Yet
authors.affiliation: From the Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan (Y.-F.W., H.-F.W., G.-L.L., J.-Y.W., S.-F.Y., K.K.W., C.-C.K.); Institute of Molecular Medicine, National Tsing Hua University, Hsinchu, Taiwan (Y.-F.W.); Division of Nephrology (Y.-J.H.), Division of Infectious Diseases and Tropical Medicine (Y.-S.Y.), Department of Medicine, Tri-Service General Hospital (Y.-J.H., Y.-S.Y.), and Graduate Institutes of Life Sciences and Biochemistry (Y.-J.H., G.-L.L., Y.-S.Y., C.-C.K.), National Defense Medical Center, Taipei, Taiwan; Metabolomic Research Center, China Medical University Hospital (S.-F.Y., K.K.W., C.-C.K.) and Graduate Institute of Basic Medical Science (S.-F.Y., K.K.W., C.-C.K.), China Medical University, Taichung, Taiwan; and Department of Medicine, University of Texas, Houston (K.K.W.). kkgo@nhri.org.tw kuocc@nhri.org.tw.
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Wu
authors.affiliation: From the Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan (Y.-F.W., H.-F.W., G.-L.L., J.-Y.W., S.-F.Y., K.K.W., C.-C.K.); Institute of Molecular Medicine, National Tsing Hua University, Hsinchu, Taiwan (Y.-F.W.); Division of Nephrology (Y.-J.H.), Division of Infectious Diseases and Tropical Medicine (Y.-S.Y.), Department of Medicine, Tri-Service General Hospital (Y.-J.H., Y.-S.Y.), and Graduate Institutes of Life Sciences and Biochemistry (Y.-J.H., G.-L.L., Y.-S.Y., C.-C.K.), National Defense Medical Center, Taipei, Taiwan; Metabolomic Research Center, China Medical University Hospital (S.-F.Y., K.K.W., C.-C.K.) and Graduate Institute of Basic Medical Science (S.-F.Y., K.K.W., C.-C.K.), China Medical University, Taichung, Taiwan; and Department of Medicine, University of Texas, Houston (K.K.W.). kkgo@nhri.org.tw kuocc@nhri.org.tw.
authors.forename: Cheng-Chin
authors.initials: CC
authors.lastname: Kuo
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000097:blood*; D004730:Endothelium, Vascular / Q000378:metabolism*; D019446:Endotoxemia / Q000097:blood* / Q000517:prevention & control*; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000097:blood
chemical_list: D000893:Anti-Inflammatory Agents; C027986:5-methoxytryptophan; D014364:Tryptophan
keywords: 5-methoxytryptophan; capillary permeability; inflammation; sepsis; shock