Cross-talk between secretory phospholipase A2 and cytosolic phospholipase A2 in rat renal mesangial cells.
Incubation of rat glomerular mesangial cells with potent proinflammatory cytokines like interleukin 1beta, (IL- 1beta) triggers the expression of a non-pancreatic secretory phospholipase A2 (sPLA2) and increases the formation of prostaglandin E2. We show here that sPLA2 acts in an autocrine fashion on mesangial cells and induces a rapid activation of protein kinase C (PKC) isoenzymes delta and epsilon and of p42 mitogen-activated protein kinase (MAPK), two putative activators of cytosolic phospholipase A2 (cPLA2). sPLA2 also activates Raf-1 kinase in mesangial cells which integrates the signals coming from PKC for further processing along the MAPK cascade. Subsequently a phosphorylation and activation of cPLA2 is observed, thus arguing for a cross-talk between the two classes of PLA2. Pretreatment of cells with either the highly specific PKC inhibitor Ro-318220 or the highly specific MAPK kinase (MEK) inhibitor PD 98059 completely blocked the sPLA2-induced cPLA2 activation, indicating that both kinases are essential for the cross-talk between the two types of PLA2. The effect of sPLA2 is mimicked by lysophosphatidylcholine (LPC), a reaction product of sPLA2 activity. LPC stimulates PKC-epsilon, Raf-1 kinase and MAPK activation as well as cPLA2 activation with a subsequent increase in arachidonic acid release from mesangial cells. These data suggest that sPLA2 by cleaving membrane phospholipids and generating LPC and other lysophospholipids activates cPLA2 via the PKC/Raf-1/MAPK signalling pathway. Hence a network of interactions between different PLA2s is operative in mesangial cells and may contribute to the progression of glomerular inflammatory processes.
Huwiler
A
A
Department of Pharmacology, Biozentrum, University of Basel, Switzerland.
Staudt
G
G
Kramer
R M
RM
Pfeilschifter
J
J
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002478:Cells, Cultured; D003600:Cytosol / Q000201:enzymology; D004789:Enzyme Activation; D005920:Glomerular Mesangium / Q000201:enzymology*; D007375:Interleukin-1 / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism; D008244:Lysophosphatidylcholines / Q000494:pharmacology; D010741:Phospholipases A / Q000378:metabolism*; D054467:Phospholipases A2; D010766:Phosphorylation; D011453:Prostaglandins / Q000096:biosynthesis; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats
D007375:Interleukin-1; D007527:Isoenzymes; D008244:Lysophosphatidylcholines; D011453:Prostaglandins; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D010741:Phospholipases A; D054467:Phospholipases A2