Glutathione peroxidase-1 primes pro-inflammatory cytokine production after LPS challenge in vivo

• Published in: PloS one 2012-03, Vol.7 (3), p.e33172-e33172
• Main Authors: Bozinovski, Steven, Seow, Huei Jiunn, Crack, Peter J, Anderson, Gary P, Vlahos, Ross
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Asthma; Biology; Bone marrow; Chemokine CXCL2 - genetics; Chemokine CXCL2 - immunology; Chemokine CXCL2 - metabolism; Cigarettes; Cytokines; Cytokines - immunology; Cytokines - metabolism; Damage assessment; Data processing; Emphysema; Enzyme Activation - genetics; Enzymes; Gelatinase; Gelatinase B; Gene expression; Glutathione; Glutathione peroxidase; Glutathione Peroxidase - deficiency; Glutathione Peroxidase - genetics; Glutathione Peroxidase - metabolism; Granulocyte-macrophage colony-stimulating factor; Granulocyte-Macrophage Colony-Stimulating Factor - genetics; Granulocyte-Macrophage Colony-Stimulating Factor - immunology; Granulocyte-Macrophage Colony-Stimulating Factor - metabolism; Granulocytes; Hydrogen peroxide; Immune response; Immune system; Inflammation; Inflammation Mediators - metabolism; Influenza; Innate immunity; Ischemia; Kinases; Lipopolysaccharides; Lipopolysaccharides - immunology; Lung; Lung diseases; Lungs; Macrophage inflammatory protein; Macrophages; Male; Mammals; Matrix Metalloproteinase 9 - genetics; Matrix Metalloproteinase 9 - metabolism; Matrix metalloproteinases; Medicine; Mice; Mice, Inbred C57BL; Mice, Knockout; Neutrophilia; Neutrophils; Oxidative stress; Oxidizing agents; Oxygen; Pathogens; Peroxidase; Pharmacology; Pneumonia - genetics; Pneumonia - immunology; Pneumonia - metabolism; Proteases; Proteasome Endopeptidase Complex - metabolism; Proteasomes; Proteinase; Proteins; Reactive oxygen species; RNA; RNA, Messenger - metabolism; Rodents; Signal Transduction; Thiols; Transcription; Tumor necrosis factor- alpha; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - immunology; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-α; Ubiquitin - metabolism
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0033172

Reactive oxygen species produced during the innate immune response to LPS are important agents of anti-pathogen defence but may also cause oxidative lung damage. Glutathione peroxidase-1 (gpx-1) is an anti-oxidant enzyme that may protect lungs from such damage. We assessed the in vivo importance of gpx-1 in LPS-induced lung inflammation. Male wild-type (WT) or gpx-1 deficient (gpx-1(-/-)) mice were treated intranasally with PBS or 10 µg LPS and killed 3 and 24 h post LPS. Lungs were lavaged with PBS and then harvested for inflammatory marker expression. LPS caused an intense neutrophilia in WT BALF evident 3 and 24 h post challenge that was reduced in gpx-1(-/-) mice. In addition, LPS-treated gpx-1(-/-) mice had significantly fewer macrophages than LPS-treated WT mice. To understand the basis for this paradoxical reduction we assessed inflammatory cytokines and proteases at protein and transcript levels. MMP-9 expression and net gelatinase activity in BALF of gpx-1(-/-) mice treated with LPS for 3 and 24 h was no different to that found in LPS-treated WT mice. BALF from LPS-treated gpx-1(-/-) mice (3 h) had less TNF-α, MIP-2 and GM-CSF protein than LPS-treated WT mice. In contrast, LPS-induced increases in TNF-α, MIP-2 and GM-CSF mRNA expression in WT mice were similar to those observed in gpx-1(-/-) mice. These attenuated protein levels were unexpectedly not mirrored by reduced mRNA transcripts but were associated with increased 20S proteasome expression. Thus, these data suggest that gpx-1 primes pro-inflammatory cytokine production after LPS challenge in vivo.