Abstract
Cathepsin B has previously been shown to proteolytically activate the proinflammatory caspase-11 in vitro. Here we show that cathepsin B is not involved in activation of caspase-11 induced by lipopolysaccharide (LPS) and subsequent maturation of interleukin (IL)-1beta in macrophages. Nevertheless, we found that the cathepsin B inhibitor benzyloxycarbonyl-Phe-Ala-fluoromethylketone (z-FA.fmk) prevents LPS-induced production of IL-1alpha, IL-1beta, and tumor necrosis factor at the transcriptional level. The latter was not because of cathepsin B inhibition, but was mediated by inhibition of the transactivation potential of the nuclear factor kappaB (NF-kappaB). z-FA.fmk did not prevent LPS-induced activation of p38 mitogen-activated protein kinase, which was shown to be involved in NF-kappaB transactivation in response to LPS. These results suggest that the previously described therapeutic effect of z-FA.fmk in the treatment of rheumatoid arthritis might not only result from inhibition of cathepsin B but also implicates an important contribution from the inhibition of NF-kappaB-dependent gene expression.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Biological Assay
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Cathepsin B / antagonists & inhibitors*
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Cell Line
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Cysteine Proteinase Inhibitors / pharmacology
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Cytokines / genetics*
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Dipeptides / pharmacology*
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Gene Expression Regulation / drug effects*
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Gene Expression Regulation / immunology
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Genes, Reporter
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Interferon-gamma / genetics
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Interleukin-1 / analysis
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Interleukin-1 / genetics
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Interleukin-6 / genetics
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Ketones / pharmacology*
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Lipopolysaccharides / pharmacology*
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Lymphocyte Activation
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Macrophages / drug effects
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Macrophages / immunology*
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Mice
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Mitogen-Activated Protein Kinases / metabolism
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NF-kappa B / metabolism
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RNA, Messenger / genetics
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T-Lymphocytes, Cytotoxic / immunology
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Transcription, Genetic / drug effects*
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Transcription, Genetic / immunology
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Transcriptional Activation / drug effects
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Transfection
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Tumor Necrosis Factor-alpha / genetics
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p38 Mitogen-Activated Protein Kinases
Substances
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Cysteine Proteinase Inhibitors
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Cytokines
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Dipeptides
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Interleukin-1
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Interleukin-6
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Ketones
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Lipopolysaccharides
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NF-kappa B
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RNA, Messenger
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Tumor Necrosis Factor-alpha
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MDL 201053
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Interferon-gamma
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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Cathepsin B