Spironolactone induces apoptosis in human mononuclear cells. Association between apoptosis and cytokine suppression |
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Authors: | M Mikkelsen S U Sønder J Nersting K Bendtzen |
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Institution: | 1. Institute for Inflammation Research, Rigshospitalet University Hospital, Blegdamsvej 9, 2100 ?, Copenhagen, Denmark 2. Institute for Inflammation Research IIR7521, Rigshospitalet University Hospital, Blegdamsvej 9, DK-2100 ?, Copenhagen, Denmark
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Abstract: | Spironolactone (SPIR) has been described to suppress accumulation of pro-inflammatory cytokines. Here, the suppression of
TNF-alpha in lipopolysaccharide (LPS)-stimulated mononuclear cell cultures was confirmed. However, SPIR was also found to
induce apoptosis, prompting the investigations of a possible association between the two effects: The apoptosis-inducing and
the cytokine-suppressive effects of SPIR correlated with regard to the effective concentration range. Also, pre-incubation
experiments demonstrated a temporal separation of the two effects of ≤4 h, with TNF-alpha suppression preceding apoptosis.
An association between the two effects was also seen when testing several SPIR analogues. Contrary to TNF-alpha, the levels
of IL-1beta increased in SPIR-treated cultures. However, the amount of IL-1beta in the supernatants depended upon the order
of SPIR and LPS addition, as IL-1beta was non-detectable in cultures treated with SPIR prior to LPS, whereas elevated IL-1beta
levels were seen when SPIR was added after LPS-stimulation. It is possible that the extracellular accumulation of IL-1beta
is due to an increased release of already produced IL-1beta as a result of cell death. In conclusion, suppression of cytokine
production by SPIR may be associated with its apoptotic potential, either directly (apoptosis is a consequence of suppressed
cytokine production, or vice-versa) or indirectly (suppressed cytokine production and apoptosis are parallel but otherwise
unrelated phenomena.) |
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Keywords: | Anti-inflammatory drugs apoptosis cytokines human mononuclear cells spironolactone spironolactone analogues (R203602 POD17/0175 POD07/0854 1N-11448 and 1N-28123) steroid hormones |
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