12/15-lipoxygenase counteracts inflammation and tissue damage in arthritis.
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.
Krönke
Gerhard
G
Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany.
Katzenbeisser
Julia
J
Uderhardt
Stefan
S
Zaiss
Mario M
MM
Scholtysek
Carina
C
Schabbauer
Gernot
G
Zarbock
Alexander
A
Koenders
Marije I
MI
Axmann
Roland
R
Zwerina
Jochen
J
Baenckler
Hans W
HW
van den Berg
Wim
W
Voll
Reinhard E
RE
Kühn
Hartmut
H
Joosten
Leo A B
LA
Schett
Georg
G
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
D015777:Eicosanoids; D018836:Inflammation Mediators; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase