Exp Mol Med.  2008 Aug;40(4):461-476. 10.3858/emm.2008.40.4.461.

Regulation of pro-inflammatory responses by lipoxygenases via intracellular reactive oxygen species in vitro and in vivo

• Kim SY
• Kim TB
• Moon KA
• Kim TJ
• Shin D
• Cho YS
• Moon HB
• Lee KY

• KMID: 1094126
• DOI: http://doi.org/10.3858/emm.2008.40.4.461

Abstract

Reactive oxygen species (ROS) performs a pivotal function as a signaling mediator in receptor-mediated signaling. However, the sources of ROS in this signaling have yet to be determined, but may include lipoxygenases (LOXs) and NADPH oxidase. The stimulation of lymphoid cells with TNF-alpha, IL-1beta, and LPS resulted in significant ROS production and NF-kappaB activation. Intriguingly, these responses were markedly abolished via treatment with the LOXs inhibitor nordihydroguaiaretic acid (NDGA). We further examined in vivo anti-inflammatory effects of NDGA in allergic airway inflammation. Both intraperitoneal and intravenous NDGA administration attenuated ovalbumin (OVA)-induced influx into the lungs of total leukocytes, as well as IL-4, IL-5, IL-13, and TNF-alpha levels. NDGA also significantly reduced serum levels of OVA-specific IgE and suppressed OVA-induced airway hyperresponsiveness to inhaled methacholine. The results of our histological studies and flow cytometric analyses showed that NDGA inhibits OVA-induced lung inflammation and the infiltration of CD11b+ macrophages into the lung. Collectively, our findings indicate that LOXs performs an essential function in pro-inflammatory signaling via the regulation of ROS regulation, and also that the inhibition of LOXs activity may have therapeutic potential with regard to the treatment of allergic airway inflammation.

Keyword

anti-inflammatory agents; asthma; lipoxygenase; macrophages; models, animal; NF-kappa B; reactive oxygen species

MeSH Terms

Animals
Antioxidants/metabolism
Asthma/complications/metabolism/pathology/physiopathology
Bronchial Hyperreactivity/drug therapy/pathology
Bronchial Provocation Tests
Bronchoalveolar Lavage Fluid/cytology
Cells, Cultured
Drug Evaluation, Preclinical
Humans
Inflammation/*etiology/metabolism
Jurkat Cells
Lipoxygenase/*physiology
Lipoxygenase Inhibitors/pharmacology/therapeutic use
Lymphocytes/drug effects/metabolism
Male
Mice
Mice, Inbred BALB C
Nordihydroguaiaretic Acid/pharmacology/therapeutic use
Reactive Oxygen Species/*adverse effects/*metabolism