The cathepsin B inhibitor z-FA.fmk inhibits cytokine production in macrophages stimulated by lipopolysaccharide.
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.
Schotte
P
P
Department of Molecular Biology, Unit for Molecular Signal Transduction in Inflammation, Flanders Interuniversity Institute for Biotechnology and Ghent University, 9000 Ghent, Belgium.
Schauvliege
R
R
Janssens
S
S
Beyaert
R
R
D000818:Animals; D001681:Biological Assay; D002401:Cathepsin B / Q000037:antagonists & inhibitors*; D002460:Cell Line; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D016207:Cytokines / Q000235:genetics*; D004151:Dipeptides / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000276:immunology; D017930:Genes, Reporter; D007371:Interferon-gamma / Q000235:genetics; D007375:Interleukin-1 / Q000032:analysis / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D007659:Ketones / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008213:Lymphocyte Activation; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014158:Transcription, Genetic / Q000187:drug effects* / Q000276:immunology; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases
D015853:Cysteine Proteinase Inhibitors; D016207:Cytokines; D004151:Dipeptides; D007375:Interleukin-1; D015850:Interleukin-6; D007659:Ketones; D008070:Lipopolysaccharides; D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C057383:MDL 201053; D007371:Interferon-gamma; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D002401:Cathepsin B