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

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-α, IL-1β, and LPS resulted in significant ROS production and NF-κB 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-α 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.

Garcinol: Current status of its anti-oxidative, anti-inflammatory and anti-cancer effects

“…Moreover, extracellular signalregulated kinase 1/2 (ERK1/2), a protein kinase of the P38/Mitogenactivated protein kinase (MAPK) family, can also mediate the inflammation process [21]. Under normal physiological conditions, phosphorylated ERK1/2 activates cytosolic phospholipases A2 (cPLA2) and leads to the formation of COX-2, an enzyme that produces prostaglandins (PGs) [22]. In lipopolysaccharide-activated macrophages, 1 μM garcinol inhibited the production of COX-2 and PGs.…”

“…A physical analysis of garcinol identified a melting point of 122°C and optical rotation of [α] 22 D − 143°(1% chloroform). The molecular formula, C38H50O6, was suggested to have structural similarities to xanthochymol (molecular mass: 602.82 and [α] 22 D +141°(1% chloroform), a prenylated chalconoid previously discovered from Garcinia xanthochymus [4]. However, based on its optical rotation sign, garcinol may be more closely associated with cambogin (molecular mass: 602.27 and [α] 22 D − 132.9°(1% chloroform) [8,9], an isoprenylated benzophenone derivative isolated from G. cambogia and characterized by Venkatsuamy et al [4,5].…”

“…It was precipitated as yellow needle-like crystals with a concentration of 1.5% in hexane [4]. A physical analysis of garcinol identified a melting point of 122°C and optical rotation of [α] 22 D − 143°(1% chloroform). The molecular formula, C38H50O6, was suggested to have structural similarities to xanthochymol (molecular mass: 602.82 and [α] 22 D +141°(1% chloroform), a prenylated chalconoid previously discovered from Garcinia xanthochymus [4].…”

Ligation of CD40 receptor in human B lymphocytes triggers the 5-lipoxygenase pathway to produce reactive oxygen species and activate p38 MAPK

“…Although these highly reactive molecules regulate many important cellular events, including transcriptional factor activation (Lo and Cruz, 1995;Sulciner et al, 1996;Bubici et al, 2006), cellular proliferation (Irani et al, 1997), and apoptosis (O'Donnell et al, 1995) in a variety of non-phagocytic cells, the generation of ROS is not yet well characterized. Recently, potential roles of the mitogenic oxidase Nox family NADPH oxidases (Lambeth et al, 2000;Petry et al, 2010) and/or 5-lipoxygenase (5-LO), which catalyzes the production of leukotrienes and ROS from arachidonic acid (Harrison and Murphy, 1995;Catalano et al, 2005;Kim et al, 2008), have been demonstrated in the generation of ROS following receptor ligation in various cell types.…”

Association between genetic variations of the transforming growth factor β receptor type III and asthma in a Korean population

“…With respect to the immunological pathogenesis of asthma, Th2 cytokines, such as IL-4, IL-5, IL-9, and IL-13, are considered to be key mediators of the development of asthma phenotypes, such as airway inflammation and AHR (Mosmann et al, 1986;Kim et al, 2008). IL-13 is now believed to be a central mediator in the development of allergic asthma (Wills-Karp et al, 1998).…”