Krönke Gerhard, Katzenbeisser Julia, Uderhardt Stefan, Zaiss Mario M, Scholtysek Carina, Schabbauer Gernot, Zarbock Alexander, Koenders Marije I, Axmann Roland, Zwerina Jochen, Baenckler Hans W, van den Berg Wim, Voll Reinhard E, Kühn Hartmut, Joosten Leo A B, Schett Georg
Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany.
J Immunol. 2009 Sep 1;183(5):3383-9. doi: 10.4049/jimmunol.0900327. Epub 2009 Aug 12.
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.
类花生酸是炎症反应的重要介质，对炎症的起始和消退均有作用。白细胞型12/15-脂氧合酶（12/15-LO）是参与生成一类类花生酸的主要酶，这类类花生酸包括抗炎性脂氧素A(4)（LXA(4)）。然而，12/15-LO对诸如关节炎等慢性炎症性疾病的影响仍不清楚。通过使用两种关节炎实验模型，即K/BxN血清转移模型和肿瘤坏死因子转基因小鼠模型，我们发现缺失12/15-LO会导致炎症失控和组织损伤。与这些发现一致，12/15-LO缺陷小鼠在发炎的滑膜内显示出炎症基因表达增强以及LXA(4)水平降低。在分离的巨噬细胞中，添加12/15-LO衍生的类花生酸可阻断p38丝裂原活化蛋白激酶的磷酸化以及一部分促炎基因的表达。相反，12/15-LO缺陷的巨噬细胞显示LXA(4)水平显著降低，这与用肿瘤坏死因子-α刺激后p38丝裂原活化蛋白激酶的激活增加以及炎症基因表达增强相关。综上所述，这些结果支持12/15-LO及其产物在诸如关节炎等慢性炎症性疾病期间具有抗炎和组织保护作用。
