Nitric oxide blocks nuclear factor-kappaB activation in alveolar macrophages.
Nitric oxide (NO) is an important endogenous regulatory molecule implicated in both proinflammatory and antiinflammatory processes in the lung. Previously, we demonstrated that in human alveolar macrophages (AM), NO decreased inflammatory cytokine production, including that of interleukin-1beta, tumor necrosis factor-alpha and macrophage inflammatory protein-1alpha. One mechanism by which NO could regulate such diverse cytokine production is through effects on the transcription factor nuclear factor-kappaB (NF-kappaB), which controls the expression of the genes for these inflammatory cytokines and growth factors. We therefore investigated whether NO affects NF-kappaB activation in AM in vitro and in vivo. In vitro studies with AM showed that NF-kappaB activation by lipopolysaccharide (LPS) is decreased by NO in a dose-dependent manner. NO prevented an LPS-mediated decrease in the NF-kappaB inhibitory protein IkappaB-alpha. In asthma, airway NO levels are increased, whereas in primary pulmonary hypertension (PPH), airway NO levels are lower than in healthy lungs. In vivo investigations were conducted with freshly isolated AM from healthy controls, asthmatic individuals, and PPH patients. Healthy individuals had airway NO levels of 8 +/- 2 ppb (mean +/- SEM), which is associated with low NF-kappaB activation. Asthma patients with airway NO levels > 17 ppb showed minimal NF-kappaB activation, whereas asthmatic individuals with NO levels </= 17 ppb showed greater NF-kappaB activation. PPH patients with low NO (1 +/- 1 ppb) had prominent NF-kappaB activation. These in vivo studies in asthma and PPH support the in vitro observation of an inverse relationship between NO and NF-kappaB activation. One mechanism by which NO blocks cytokine production involves IkappaB.
Raychaudhuri
B
B
Departments of Pulmonary and Critical Care Medicine, Neurosciences, Cancer Biology, and Immunology, The Cleveland Clinic Foundation, Cleveland, Ohio, USA.
Dweik
R
R
Connors
M J
MJ
Buhrow
L
L
Malur
A
A
Drazba
J
J
Arroliga
A C
AC
Erzurum
S C
SC
Kavuru
M S
MS
Thomassen
M J
MJ
D001249:Asthma / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D016022:Case-Control Studies; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D016676:Macrophages, Alveolar / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D009569:Nitric Oxide / Q000494:pharmacology* / Q000502:physiology*; D009603:Nitroso Compounds / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D008070:Lipopolysaccharides; D016328:NF-kappa B; D009603:Nitroso Compounds; D014409:Tumor Necrosis Factor-alpha; C094210:2,2'-(hydroxynitrosohydrazono)bis-ethanamine; D009569:Nitric Oxide