Spironolactone induces apoptosis in human mononuclear cells. Association between apoptosis and cytokine suppression.
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 < or = 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).
Mikkelsen
M
M
Institute for Inflammation Research, Rigshospitalet University Hospital, Blegdamsvej 9, 2100 Ø, Copenhagen, Denmark.
Sønder
S U
SU
Nersting
J
J
Bendtzen
K
K
D017209:Apoptosis; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism; D007700:Kinetics; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000276:immunology; D013148:Spironolactone / Q000031:analogs & derivatives / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D013148:Spironolactone