title: Glutathione peroxidase-1 primes pro-inflammatory cytokine production after LPS challenge in vivo.
abstract: 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.
authors.affiliation: Department of Pharmacology, The University of Melbourne, Victoria, Australia.
authors.forename: Steven
authors.initials: S
authors.lastname: Bozinovski
authors.forename: Huei Jiunn
authors.initials: HJ
authors.lastname: Seow
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Crack
authors.forename: Gary P
authors.initials: GP
authors.lastname: Anderson
authors.forename: Ross
authors.initials: R
authors.lastname: Vlahos
mesh_terms: D000818:Animals; D054426:Chemokine CXCL2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000276:immunology / Q000378:metabolism*; D004789:Enzyme Activation / Q000235:genetics; D005979:Glutathione Peroxidase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000276:immunology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011014:Pneumonia / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D000094765:Glutathione Peroxidase GPX1
chemical_list: D054426:Chemokine CXCL2; D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D025801:Ubiquitin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D005979:Glutathione Peroxidase; D020780:Matrix Metalloproteinase 9; D046988:Proteasome Endopeptidase Complex; D000094765:Glutathione Peroxidase GPX1; C000722068:Gpx1 protein, mouse