Modulation of cytokine-induced expression of secretory phospholipase A2-type IIA by protein kinase C in rat renal mesangial cells.
Renal mesangial cells express the 14 kDa secretory phospholipase A2-type IIA (sPLA2-IIA) in response to interleukin-1beta (IL-1beta). In order to understand the regulation of cytokine-induced sPLA2-IIA induction in more detail, we investigated whether phorbol ester-activated protein kinase C (PKC) has an influence on the IL-1beta-induced expression of sPLA2-IIA. We found that treatment of mesangial cells with the biologically active phorbol 12-myristate 13-acetate (PMA) and phorbol 12,13-dibutyrate inhibited IL-1beta induction of sPLA2-IIA mRNA, protein, and activity, whereas the inactive compound 4alpha-phorbol 12,13-didecanoate was without effect. An 8-hr pretreatment with PMA, which led to down-regulation of PKC-alpha and -delta isoenzymes, still inhibited sPLA2-IIA induction. Only after down-regulation of PKC-epsilon isoenzyme by 24-hr preincubation with PMA were we able to reconstitute the IL-1beta-induced sPLA2-IIA expression. Thrombin as a physiological activator of PKC in mesangial cells exerted similar effects as PMA and inhibited sPLA2-IIA expression. The selective PKC inhibitor calphostin C potentiated IL-1beta induction of sPLA2-IIA mRNA levels and partially reconstituted the thrombin-induced inhibition of sPLA2-IIA mRNA and activity. These data show that IL-1beta induction of sPLA2-IIA can be modulated by PKC and that the epsilon-isoenzyme of the PKC family is the most likely candidate mediating the suppression of cytokine-induced sPLA2-IIA expression in mesangial cells.
Scholz
K
K
Zentrum der Pharmakologie, Klinikum der Johann Wolfgang Goethe-Universitat, Frankfurt am Main, Germany.
Vlachojannis
G J
GJ
Spitzer
S
S
Schini-Kerth
V
V
Van Den Bosch
H
H
Kaszkin
M
M
Pfeilschifter
J
J
D000818:Animals; D002478:Cells, Cultured; D015536:Down-Regulation; D004347:Drug Interactions; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D054501:Group II Phospholipases A2; D007375:Interleukin-1 / Q000378:metabolism*; D009281:Naphthalenes / Q000494:pharmacology; D010703:Phorbol Esters / Q000494:pharmacology; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D054467:Phospholipases A2; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D013917:Thrombin / Q000494:pharmacology
D004791:Enzyme Inhibitors; D007375:Interleukin-1; D009281:Naphthalenes; D010703:Phorbol Esters; D012333:RNA, Messenger; D011493:Protein Kinase C; D010741:Phospholipases A; D054501:Group II Phospholipases A2; D054467:Phospholipases A2; D013917:Thrombin; C058819:calphostin C