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*
Department of Medicine B,
Institute for Immunology, University of Münster, Münster, Germany
Glucocorticoids (GC) are potent anti-inflammatory and
immunosuppressive agents that act on a variety of immune cells,
including monocytes and macrophages. However, the exact cellular
mechanisms underlying this anti-inflammatory capacity are still
unknown. In our study, we determined the induction of apoptosis by GC
in human monocytes. Peripheral blood monocytes were isolated by density
centrifugation methods with a purity of >90% and were cultured in
RPMI 1640 medium. Monocyte apoptosis was determined by four independent
methods, including annexin-V staining, TUNEL, DNA-laddering, and
typical morphology by means of transmission electron microscopy.
TNF-
and IL-1ß were measured by ELISA. GC receptor was blocked
with mifepristone. Caspase 3 was inhibited with caspase-3 inhibitor
(DEVD-CHO). Stimulation with different GC at therapeutic concentrations
resulted in monocyte apoptosis in a time- and dose-dependent manner.
Necrosis was excluded by propidium iodide staining. Proinflammatory
cytokines such as IL-1ß and TNF- were down-regulated by GC
treatment. Continuous treatment of monocytes with IL-1ß, but not with
TNF-, could almost completely prevent GC-induced cell death. The
addition of mifepristone or caspase-3 inhibitor could partially
abrogate GC-induced apoptosis as well as GC-induced inhibition of
IL-1ß. This is the first study to demonstrate induction of apoptosis
by GC in human monocytes. GC-induced monocyte apoptosis may be
partially mediated through effects on IL-1ß production. It is
conceivable that GC exert their anti-inflammatory capacity in
various diseases, at least in part, by the induction of apoptosis in
monocytes.
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