Lipopolysaccharide-induced NF-kappaB activation and cytokine release in human alveolar macrophages is PKC-independent and TK- and PC-PLC-dependent.
A critical feature of sepsis-induced adult respiratory distress syndrome (ARDS) is the release of cytokines (such as interleukin [IL]-6, IL-8, and tumor necrosis factor [TNF]) from endotoxin (lipopolysaccharide [LPS])-activated alveolar macrophages (AM). Nuclear factor kappa B (NF-kappaB) is activated in AM from patients with ARDS, and it is essential for the transcription of many cytokine genes. In these studies, we evaluated the regulation of LPS-induced cytokine release and the activation of NF-kappaB in human AM. We found that the activation of NF-kappaB and the release of IL-6, IL-8, and TNF from AM exposed to LPS was protein kinase C-independent and tyrosine kinase- and phosphatidylcholine-specific phospholipase C-dependent. We also found that LPS-induced activation of NF-kappaB was enhanced in AM cultured in serum or in the presence of LPS-binding protein, simulating conditions in the lung that are present in ARDS. In addition, LPS triggered the activation of several different NF-kappaB complexes in AM, and different forms of NF-kappaB bound to the IL-6, IL-8, and TNF promoter sequences. These observations suggest that physiologic abnormalities present in the lungs of patients with ARDS facilitate the activation of NF-kappaB and local release of cytokines.
Carter
A B
AB
Department of Medicine, University of Iowa College of Medicine, Iowa City, IA 52242, USA. aaron-carter@uiowa.edu
Monick
M M
MM
Hunninghake
G W
GW
D000209:Acute-Phase Proteins; D000293:Adolescent; D000328:Adult; D002352:Carrier Proteins / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D006801:Humans; D008070:Lipopolysaccharides / Q000276:immunology*; D016676:Macrophages, Alveolar / Q000276:immunology*; D008562:Membrane Glycoproteins; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism*; D011485:Protein Binding; D011493:Protein Kinase C / Q000378:metabolism; D012128:Respiratory Distress Syndrome / Q000209:etiology; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D010738:Type C Phospholipases / Q000378:metabolism; D000099231:Lipopolysaccharide-Binding Protein
D000209:Acute-Phase Proteins; D002352:Carrier Proteins; D016207:Cytokines; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011493:Protein Kinase C; D014409:Tumor Necrosis Factor-alpha; D010738:Type C Phospholipases; D000099231:Lipopolysaccharide-Binding Protein; C105598:phosphatidylcholine-specific phospholipase C