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15-Epi-lipoxin A4 inhibits human neutrophil superoxide anion generation by regulating polyisoprenyl diphosphate phosphatase 1.

ABSTRACT: Regulation of leukocyte activation is critical to limit unintended tissue injury during acute inflammation. On neutrophil activation, polyisoprenyl diphosphate phosphatase 1 (PDP1) rapidly converts presqualene diphosphate to presqualene monophosphate to facilitate cell activation. Lipoxins are potent anti-inflammatory mediators for neutrophils, yet their counterregulatory signaling mechanisms remain to be determined. 15-Epi-lipoxin A4 (15-epi-LXA4) blocked agonist-initiated association of the nicotinamide adenine dinucleotide phosphate oxidase components p47(PHOX) and p22(PHOX) in human neutrophils. 15-Epi-LXA4 (0.1-100 nM) inhibited neutrophil superoxide anion (O2(-)) generation in a concentration- and ALX/FPR2 receptor-dependent manner that was disrupted by PDP1-specific antibodies. In differentiated HL60 cells, a myeloid cell line, agonist-initiated O2(-) generation was inhibited by PDP1 siRNA. Recombinant human PDP1 was directly phosphorylated in vitro by select protein kinase C (PKC) isoforms, including PKC?II. When neutrophils were exposed to formyl-methionyl-leucyl-phenylalanine (fMLP), PKC?II was rapidly phosphorylated and physically associated with PDP1. Agonist-initiated conversion of neutrophil presqualene diphosphate to presqualene monophosphate was blocked by PKC?II inhibition. Neutrophil exposure to 15-epi-LXA4 attenuated fMLP triggered PKC?II phosphorylation and its interactions with PDP1. Together, these findings indicate that PDP1 serves an integral signaling role in neutrophil proinflammatory responses and as a target for counter-regulatory mediators.

SUBMITTER: Carlo T

PROVIDER: S-EPMC3688747 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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15-Epi-lipoxin A4 inhibits human neutrophil superoxide anion generation by regulating polyisoprenyl diphosphate phosphatase 1.

Carlo Troy T Kalwa Hermann H Levy Bruce D BD

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20130408 7

Regulation of leukocyte activation is critical to limit unintended tissue injury during acute inflammation. On neutrophil activation, polyisoprenyl diphosphate phosphatase 1 (PDP1) rapidly converts presqualene diphosphate to presqualene monophosphate to facilitate cell activation. Lipoxins are potent anti-inflammatory mediators for neutrophils, yet their counterregulatory signaling mechanisms remain to be determined. 15-Epi-lipoxin A4 (15-epi-LXA4) blocked agonist-initiated association of the ni ...[more]

PMID: 23568778

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Project description:Trypanosoma cruzi is the causal agent of Chagas Disease that is endemic in Latin American, afflicting more than ten million people approximately. This disease has two phases, acute and chronic. The acute phase is often asymptomatic, but with time it progresses to the chronic phase, affecting the heart and gastrointestinal tract and can be lethal. Chronic Chagas cardiomyopathy involves an inflammatory vasculopathy. Endothelial activation during Chagas disease entails the expression of cell adhesion molecules such as E-selectin, vascular cell adhesion molecule-1 (VCAM-1) and intercellular cell adhesion molecule-1 (ICAM-1) through a mechanism involving NF-κB activation. Currently, specific trypanocidal therapy remains on benznidazole, although new triazole derivatives are promising. A novel strategy is proposed that aims at some pathophysiological processes to facilitate current antiparasitic therapy, decreasing treatment length or doses and slowing disease progress. Simvastatin has anti-inflammatory actions, including improvement of endothelial function, by inducing a novel pro-resolving lipid, the 5-lypoxygenase derivative 15-epi-lipoxin A4 (15-epi-LXA4), which belongs to aspirin-triggered lipoxins. Herein, we propose modifying endothelial activation with simvastatin or benznidazole and evaluate the pathways involved, including induction of 15-epi-LXA4. The effect of 5 μM simvastatin or 20 μM benznidazole upon endothelial activation was assessed in EA.hy926 or HUVEC cells, by E-selectin, ICAM-1 and VCAM-1 expression. 15-epi-LXA4 production and the relationship of both drugs with the NFκB pathway, as measured by IKK-IKB phosphorylation and nuclear migration of p65 protein was also assayed. Both drugs were administered to cell cultures 16 hours before the infection with T. cruzi parasites. Indeed, 5 μM simvastatin as well as 20 μM benznidazole prevented the increase in E-selectin, ICAM-1 and VCAM-1 expression in T. cruzi-infected endothelial cells by decreasing the NF-κB pathway. In conclusion, Simvastatin and benznidazole prevent endothelial activation induced by T. cruzi infection, and the effect of simvastatin is mediated by the inhibition of the NFκB pathway by inducing 15-epi-LXA4 production.

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15-Epi-lipoxin A4 inhibits human neutrophil superoxide anion generation by regulating polyisoprenyl diphosphate phosphatase 1.

Publications

15-Epi-lipoxin A4 inhibits human neutrophil superoxide anion generation by regulating polyisoprenyl diphosphate phosphatase 1.

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