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Antineutrophil cytoplasm antibody-induced neutrophil nitric oxide production is nitric oxide synthase independent.

Abstract：

BACKGROUND:Antineutrophil cytoplasm antibodies (ANCAs) are implicated in the pathogenesis of systemic vasculitis. We asked whether ANCA could induce nitric oxide (NO) release from human neutrophils and, if so, whether this NO production was dependent on NO synthase (NOS) activity. METHODS:Neutrophil NO production was measured using a chemiluminescence assay, and NOS activity was determined by the conversion of [(14)C] L-arginine to [(14)C] L-citrulline and NOS mRNA expression by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS:Human neutrophils isolated from healthy donors were incubated at 37 degrees C with human ANCA, normal human IgG, murine monoclonal myeloperoxidase ANCA, murine proteinase-3 ANCA, or their respective isotypic controls for 6 to 12 hours in RPMI. Both human and monoclonal ANCA led to a dose-dependent increase of NO compared with control IgG. Neutrophils, either freshly isolated or incubated for seven hours with murine monoclonal myeloperoxidase ANCA, proteinase-3 ANCA, or a mixture of interleukin-1 beta, tumor necrosis factor-alpha, interferon-gamma plus lipopolysaccharide showed no NOS activity with low conversion rates of [(14)C] L-arginine to [(14)C] L-citrulline, which could not be inhibited by N(G)-monomethyl-L-arginine (NOS inhibitor). To detect NOS mRNA expression, RT-PCR was performed using oligonucleotide primers derived from mRNA sequences of either human constitutive endothelial NOS (eNOS), constitutive neuroneal NOS (nNOS), or human hepatocyte inducible NOS (iNOS). There was no expression of either eNOS, nNOS, or iNOS in untreated, human and murine monoclonal ANCA-treated, or cytokine-treated neutrophils. CONCLUSION:These data suggest that human neutrophils produce NO in response to ANCA but in a NOS-independent way. NO can be generated from a nonenzymatic interaction between hydrogen peroxide and arginine. We postulate that this is the predominant pathway of NO synthesis in neutrophils, since ANCAs are capable of inducing reactive oxygen species production from neutrophils.

journal_name

Kidney Int

journal_title

Kidney international

authors

Tse WY,Williams J,Pall A,Wilkes M,Savage CO,Adu D

doi

10.1046/j.1523-1755.2001.059002593.x

subject

Has Abstract

pub_date

2001-02-01 00:00:00

pages

593-600

issue

eissn

0085-2538

issn

1523-1755

pii

S0085-2538(15)47508-8

journal_volume

pub_type

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Antineutrophil cytoplasm antibody-induced neutrophil nitric oxide production is nitric oxide synthase independent.