Aspirin inhibits expression of the interleukin-1beta-inducible group II phospholipase A2.
Nonsteroidal anti-inflammatory drugs (NSAIDs) clearly inhibit the synthesis and release of prostaglandins. However, these actions are not sufficient to explain all the anti-inflammatory effects of these drugs. Recently, it has been shown that aspirin and sodium salicylate inhibit the activation of the transcription factor NF-kappaB. Group II phospholipase A2 (sPLA2) is expressed in rat glomerular mesangial cells upon exposure to the inflammatory cytokine interleukin-1beta (IL-1beta) and this induction is attenuated by the NF-kappaB inhibitor pyrrolidine dithiocarbamate (PDTC). We now report that aspirin inhibits the IL-1beta-induced sPLA2 activity in rat mesangial cells in a dose-dependent manner. The IC50 value of aspirin for sPLA2 inhibition was 6.5 mM. This decrease in sPLA2 activity was not due to direct inhibition of enzymatic activity but rather to the fact that aspirin inhibits the expression of IL-1beta-induced sPLA2 protein and mRNA. Furthermore, by electrophoretic mobility shift analysis we demonstrate reduced DNA binding of the nuclear factor kappaB, an essential component of the IL-1beta-dependent upregulation of sPLA2 gene transcription, after treatment of the cells with aspirin. The study described in this report indicates that the inhibition of sPLA2 expression as induced by pro-inflammatory cytokines potentially represents an additional mechanism of action for aspirin.
Vervoordeldonk
M J
MJ
Centre for Biomembranes and Lipid Enzymology, Institute for Biomembranes, Utrecht, The Netherlands.
Pineda Torra
I M
IM
Aarsman
A J
AJ
van den Bosch
H
H
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology*; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004790:Enzyme Induction / Q000187:drug effects; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D007375:Interleukin-1 / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D054467:Phospholipases A2; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007375:Interleukin-1; D016328:NF-kappa B; D012333:RNA, Messenger; D004247:DNA; D010741:Phospholipases A; D054467:Phospholipases A2; D001241:Aspirin