Abstract
Fibroblast apoptosis is crucial to the resolution of fibrosis. However, the mechanisms by which these cells undergo apoptosis are not well known. Because interleukin (IL)-6 and IL-11 may alter repair and remodeling processes, we hypothesized that they may play a role in idiopathic pulmonary fibrosis (IPF). We investigated the effects of these cytokines on Fas-induced apoptosis using primary lung fibroblasts from three patients with IPF (IPF-Fb) and three subjects without lung disease (normal-Fb). IPF-Fb were resistant to Fas-induced apoptosis compared with normal-Fb (P < 0.01). Using RNase protection assays, we showed that IL-6 enhanced Fas-induced apoptosis and expression of Bax in normal-Fb, but inhibited apoptosis and induced expression of Bcl-2 in IPF-Fb. Densitometry of Western blots revealed a Bcl-2/Bax ratio 0.15 +/- 0.01 in normal-Fb compared with 12.05 +/- 1.0 in IPF-Fb. Upregulation of Bcl-2 in normal-Fb and Bax in IPF-Fb were both STAT-3-dependent. Inhibition of extracellular signal-regulated kinase had no effect in normal-Fb, but reversed the antiapoptotic effect of IL-6 in IPF-Fb. IL-11 inhibited Fas-induced apoptosis and increased Bcl-2 expression in both normal-Fb and IPF-Fb. These results suggest that altered IL-6 signaling in IPF-Fb may enhance the resistance of these cells to apoptosis and contribute to a profibrotic effect of IL-6 in IPF.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / drug effects
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Apoptosis / immunology*
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Cells, Cultured
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DNA-Binding Proteins / antagonists & inhibitors
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DNA-Binding Proteins / metabolism
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Enzyme Inhibitors / pharmacology
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Fas Ligand Protein
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Fibroblasts / drug effects*
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Fibroblasts / immunology
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Humans
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Interleukin-11 / immunology
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Interleukin-11 / pharmacology
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Interleukin-6 / immunology*
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Interleukin-6 / pharmacology
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Lung / drug effects
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Lung / immunology*
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Lung / physiopathology
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MAP Kinase Signaling System / drug effects
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MAP Kinase Signaling System / immunology
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Membrane Glycoproteins / immunology
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Membrane Glycoproteins / pharmacology
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Proto-Oncogene Proteins / drug effects
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Proto-Oncogene Proteins / immunology
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Proto-Oncogene Proteins c-bcl-2 / drug effects
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Proto-Oncogene Proteins c-bcl-2 / immunology
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Pulmonary Fibrosis / chemically induced
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Pulmonary Fibrosis / immunology*
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Pulmonary Fibrosis / physiopathology
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STAT3 Transcription Factor
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Trans-Activators / antagonists & inhibitors
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Trans-Activators / metabolism
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bcl-2-Associated X Protein
Substances
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BAX protein, human
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DNA-Binding Proteins
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Enzyme Inhibitors
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FASLG protein, human
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Fas Ligand Protein
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Interleukin-11
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Interleukin-6
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Membrane Glycoproteins
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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STAT3 Transcription Factor
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STAT3 protein, human
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Trans-Activators
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bcl-2-Associated X Protein