title: 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 PKCβII. When neutrophils were exposed to formyl-methionyl-leucyl-phenylalanine (fMLP), PKCβII was rapidly phosphorylated and physically associated with PDP1. Agonist-initiated conversion of neutrophil presqualene diphosphate to presqualene monophosphate was blocked by PKCβII inhibition. Neutrophil exposure to 15-epi-LXA4 attenuated fMLP triggered PKCβII 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.
authors.affiliation: Pulmonary and Critical Care Medicine Division, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Troy
authors.initials: T
authors.lastname: Carlo
authors.forename: Hermann
authors.initials: H
authors.lastname: Kalwa
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Levy
mesh_terms: D015153:Blotting, Western; D004305:Dose-Response Relationship, Drug; D018922:HL-60 Cells; D006801:Humans; D044045:Lipoxins / Q000494:pharmacology*; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D019255:NADPH Oxidases / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011106:Polyisoprenyl Phosphates / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D064546:Protein Kinase C beta; D034622:RNA Interference; D011994:Recombinant Proteins / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*
chemical_list: D044045:Lipoxins; D011106:Polyisoprenyl Phosphates; D011994:Recombinant Proteins; C040527:lipoxin A4; C108829:presqualene monophosphate; D013481:Superoxides; C017672:presqualene pyrophosphate; D009240:N-Formylmethionine Leucyl-Phenylalanine; D019255:NADPH Oxidases; C086986:CYBA protein, human; C060505:neutrophil cytosolic factor 1; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D010744:Phosphoric Monoester Hydrolases; C020088:dolichyl-phosphatase
keywords: anti-inflammatory; inflammation; lipid mediators; resolution