title: 12/15-lipoxygenase counteracts inflammation and tissue damage in arthritis.
abstract: Eicosanoids are essential mediators of the inflammatory response and contribute both to the initiation and the resolution of inflammation. Leukocyte-type 12/15-lipoxygenase (12/15-LO) represents a major enzyme involved in the generation of a subclass of eicosanoids, including the anti-inflammatory lipoxin A(4) (LXA(4)). Nevertheless, the impact of 12/15-LO on chronic inflammatory diseases such as arthritis has remained elusive. By using two experimental models of arthritis, the K/BxN serum-transfer and a TNF transgenic mouse model, we show that deletion of 12/15-LO leads to uncontrolled inflammation and tissue damage. Consistent with these findings, 12/15-LO-deficient mice showed enhanced inflammatory gene expression and decreased levels of LXA(4) within their inflamed synovia. In isolated macrophages, the addition of 12/15-LO-derived eicosanoids blocked both phosphorylation of p38MAPK and expression of a subset of proinflammatory genes. Conversely, 12/15-LO-deficient macrophages displayed significantly reduced levels of LXA(4), which correlated with increased activation of p38MAPK and an enhanced inflammatory gene expression after stimulation with TNF-alpha. Taken together, these results support an anti-inflammatory and tissue-protective role of 12/15-LO and its products during chronic inflammatory disorders such as arthritis.
authors.affiliation: Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Krönke
authors.forename: Julia
authors.initials: J
authors.lastname: Katzenbeisser
authors.forename: Stefan
authors.initials: S
authors.lastname: Uderhardt
authors.forename: Mario M
authors.initials: MM
authors.lastname: Zaiss
authors.forename: Carina
authors.initials: C
authors.lastname: Scholtysek
authors.forename: Gernot
authors.initials: G
authors.lastname: Schabbauer
authors.forename: Alexander
authors.initials: A
authors.lastname: Zarbock
authors.forename: Marije I
authors.initials: MI
authors.lastname: Koenders
authors.forename: Roland
authors.initials: R
authors.lastname: Axmann
authors.forename: Jochen
authors.initials: J
authors.lastname: Zwerina
authors.forename: Hans W
authors.initials: HW
authors.lastname: Baenckler
authors.forename: Wim
authors.initials: W
authors.lastname: van den Berg
authors.forename: Reinhard E
authors.initials: RE
authors.lastname: Voll
authors.forename: Hartmut
authors.initials: H
authors.lastname: Kühn
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
mesh_terms: D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D001093:Arachidonate 15-Lipoxygenase / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D001169:Arthritis, Experimental / Q000201:enzymology* / Q000276:immunology / Q000473:pathology*; D002908:Chronic Disease; D015777:Eicosanoids / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D025461:Feedback, Physiological / Q000276:immunology; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000502:physiology*; D007719:Knee Joint / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009928:Organ Specificity / Q000235:genetics / Q000276:immunology
chemical_list: D015777:Eicosanoids; D018836:Inflammation Mediators; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase