Author(s):
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Kronke, G.; Katzenbeisser, J.; Uderhardt, S.; Zaiss, M.M.; Scholtysek, C.; Schabbauer, G.; Zarbock, A.;
Koenders, M.I.
; Axmann, R.; Zwerina, J.; Baenckler, H.W.;
Berg, W.B. van den
; Voll, R.E.; Kuhn, H.;
Joosten, L.A.B.
; Schett, G.
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Subject:
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N4i 1: Pathogenesis and modulation of inflammation N4i 4: Auto-immunity, transplantation and immunotherapy NCMLS 1: Infection and autoimmunity |
Organization:
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Rheumatology Neurology Internal Medicine |
Abstract:
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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.
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