Lipopolysaccharide-induced NF-κB 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-kappa B) 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-kappa B in human AM. We found that the activation of NF-kappa B 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-kappa B 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-kappa B complexes in AM, and different forms of NF-KB 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-KB and local release of cytokines.