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15‐Epi‐lipoxin A 4 inhibits human neutrophil superoxide anion generation by regulating polyisoprenyl diphosphate phosphatase 1
Author(s) -
Carlo Troy,
Kalwa Hermann,
Levy Bruce D.
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.12-223982
Subject(s) - superoxide , p22phox , nadph oxidase , chemistry , agonist , phosphatase , phosphorylation , protein kinase c , biochemistry , microbiology and biotechnology , receptor , biology , reactive oxygen species , enzyme
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 A 4 (15‐epi‐LXA 4 ) blocked agonist‐initiated association of the nicotinamide adenine dinucleotide phosphate oxidase components p47 PHOX and p22 PHOX in human neutrophils. 15‐Epi‐LXA 4 (0.1‐100 nM) inhibited neutrophil superoxide anion (O 2 – ) 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 O 2 – 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‐leucylphenylalanine ( f MLP), 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‐LXA 4 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.—Carlo, T., Kalwa, H., Levy, B. D. 15‐Epi‐lipoxin A 4 inhibits human neutrophil superoxide anion generation by regulating polyisoprenyl diphosphate phosphatase 1. FASEB J. 27, 2733‐2741 (2013). www.fasebj.org