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Lipopolysaccharide Activates Caspase-1 (Interleukin-1-Converting
Enzyme) in Cultured Monocytic and Endothelial Cells
Ralf R. Schumann,
Claus Belka,
Dirk Reuter,
Norbert Lamping,
Carsten J. Kirschning,
Joerg R. Weber, and
Dagmar Pfeil
From the Molecular Sepsis Research Laboratory,
Max-Delbrück-Center for Molecular Medicine, the Institute of
Microbiology and Hygiene, and the Department of Neurology, University
Hospital Charité, Humboldt-University, Berlin, Germany; and the
Department of Radiation Therapy, University of Tübingen,
Tübingen, Germany.
Interleukin-1 (IL-1) is a pleiotropic proinflammatory
cytokine. Mechanisms leading to its secretion include not only release of newly synthesized protein, but also cleavage of a preformed immature
precursor protein into an active secretory form by the intracellular
protease caspase-1 (formerly termed IL-1-converting enzyme [ICE]).
Caspase-1 belongs to a rapidly growing family of cysteine proteases
with substrate specificity for aspartate involved in cellular
apoptosis. We have used an assay determining the caspase-1 activity
based on cleavage of a fluorogenic peptide substrate to elucidate its
role in lipopolysaccharide (LPS)-induced secretion of IL-1. We show
that LPS induces moderate caspase-1 activity in the monocytic cell line
THP-1, in freshly isolated peripheral blood monocytes, and in human
umbilical vein endothelial cells (HUVECs) in a time- and dose-dependent
fashion. Caspase-1 activation by LPS was associated with cleavage of
the IL-1 precursor protein that was followed by release of the
mature IL-1 protein in monocytic cells. In contrast, subsequent
release of IL-1 by HUVECs was not significant. LPS-induced caspase-1
activation appeared not to result from modulation of caspase-1
transcript accumulation and inhibition of caspase-1 activity was
accomplished by two specific inhibitors, YVAD-CHO and YVAD-CMK, capable
of alleviating the release of mature IL-1. Taken together, these
results show that LPS moderately activates caspase-1 and
that caspase-1 activation contributes to LPS induction of IL-1
secretion.
Blood, Vol. 91 No. 2 (January 15), 1998:
pp. 577-584
© 1998 by The American Society of Hematology.
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