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Apoptosis in human alveolar macrophages is induced by endotoxin and is modulated by cytokines
R Bingisser1, C Stey, M Weller
1Department of Internal Medicine, University Hospital, University of Zurich, Switzerland.
Abstract:
A central factor in the pathogenesis of inflammatory and fibrotic lung disease (adult respiratory distress syndrome, sarcoidosis, idiopathic pulmonary fibrosis) is the locally elevated number of alveolar macrophages (AM). An elevation in the production rate of AM, chemoattraction and differentiation of monocytes, or a diminution in the death rate might be underlying mechanisms. The aim of the present study was to investigate the modulatory role of endotoxin and cytokines on the death rate of human AM. Lipopolysaccharide (LPS) treatment resulted in a 4-fold increase (7.6 to 30.2%) of AM death. AM death was apoptotic as assessed by in situ DNA end labeling (ISDE), transmission electron microscopy, DNA gel electrophoresis, fluorometry of fragmented DNA, and an ELISA specific for histone-associated DNA fragments. Among the different bacterial cell wall components tested, LPS was the only inducer of apoptosis in human AM. None of the tested cytokines (interleukin-1 beta [IL-1 beta], IL-4, IL-6, IL-10, tumor necrosis factor-alpha [TNF-alpha], transforming growth factor-beta 2 [TGF-beta 2], interferon-gamma [IFN-gamma], macrophage colony-stimulating factor [M-CSF], granulocyte colony-stimulating factor [G-CSF], and granulocyte-macrophage colony-stimulating factor [GM-CSF]) was capable of enhancing the spontaneous rate of apoptosis. However, LPS-induced apoptosis was significantly enhanced by the macrophage-activating cytokine IFN-gamma, and reduced by the macrophage-deactivating cytokines IL-4, IL-10, and TGF-beta.
Insights
Lipopolysaccharide (LPS) significantly increases alveolar macrophage (AM) death, inducing apoptosis. This effect is modulated by specific cytokines, with IFN-gamma enhancing and IL-4, IL-10, and TGF-beta reducing LPS-induced AM apoptosis.
Area of Science:
- Pulmonary Medicine
- Immunology
- Cell Biology
Background:
- Alveolar macrophages (AM) accumulation is key in lung diseases like IPF.
- Mechanisms include altered AM production, chemoattraction, or reduced death rates.
Purpose of the Study:
- To investigate how endotoxin and cytokines affect human AM death rates.
- To understand the role of lipopolysaccharide (LPS) and cytokines in AM apoptosis.
Main Methods:
- Human AM were treated with LPS and various cytokines.
- Apoptosis was assessed using DNA end labeling, electron microscopy, DNA gel electrophoresis, fluorometry, and ELISA.
Main Results:
- LPS treatment increased AM death by 4-fold, confirming apoptosis.
- LPS was the sole bacterial component inducing AM apoptosis.
- IFN-gamma enhanced LPS-induced apoptosis, while IL-4, IL-10, and TGF-beta reduced it.
Conclusions:
- LPS is a potent inducer of apoptosis in human AM.
- Cytokines differentially modulate LPS-induced AM apoptosis, impacting inflammatory lung disease pathogenesis.