Aryl hydrocarbon receptor-deficient mice develop heightened inflammatory responses to cigarette smoke and endotoxin associated with rapid loss of the nuclear factor-kappaB component RelB.
The transcription factor aryl hydrocarbon receptor (AhR) plays an important role in the response to environmental pollutants. However, its role in normal physiology is unclear. To investigate the role of AhR in acute lung inflammation, control and AhR knockout (KO) mice were exposed to inhaled cigarette smoke or bacterial endotoxin. Smoke-induced lung inflammation was twofold to threefold more severe in AhR KO mice than controls. Intriguingly, levels of tumor necrosis factor-alpha and interleukin-6 in the bronchoalveolar lavage of air-exposed KO mice were equal to the levels seen in smoke-exposed controls, suggesting that AhR-deficient mice are inflammation prone. AhR KO mice challenged with inhaled endotoxin, which does not contain AhR ligands, also developed greater lung neutrophilia than controls, and bronchoalveolar lavage cells from AhR KO mice produced elevated levels of tumor necrosis factor-alpha and interleukin-6 when treated with endotoxin in vitro. Nuclear factor-kappaB DNA-binding activity was elevated in smoke-exposed AhR KO mice compared with controls and was associated with a rapid loss of RelB only in the KO mice. We propose that AhR is a previously unrecognized regulator of inflammation that interacts with nuclear factor-kappaB so that in the absence of AhR RelB is prematurely degraded, resulting in heightened inflammatory responses to multiple proinflam-matory stimuli.
Thatcher
Thomas H
TH
Department of Medicine, University of Rochester, Rochester, New York 14642, USA.
Maggirwar
Sanjay B
SB
Baglole
Carolyn J
CJ
Lakatos
Heather F
HF
Gasiewicz
Thomas A
TA
Phipps
Richard P
RP
Sime
Patricia J
PJ
D000818:Animals; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000276:immunology; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D007249:Inflammation / Q000276:immunology / Q000473:pathology*; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000172:deficiency*; D051841:Transcription Factor RelB / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D018336:Receptors, Aryl Hydrocarbon; C497594:Relb protein, mouse; D014409:Tumor Necrosis Factor-alpha; D051841:Transcription Factor RelB