Cross-talk between secretory phospholipase A 2 and cytosolic phospholipase A 2 in rat renal mesangial cells

Abstract

Incubation of rat glomerular mesangial cells with potent proinflammatory cytokines like interleukin 1 β (IL-1 β) triggers the expression of a non-pancreatic secretory phospholipase A 2 (sPLA 2) and increases the formation of prostaglandin E 2. We show here that sPLA 2 acts in an autocrine fashion on mesangial cells and induces a rapid activation of protein kinase C (PKC) isoenzymes δ and ϵ and of p42 mitogen-activated protein kinase (MAPK), two putative activators of cytosolic phospholipase A 2 (cPLA 2). sPLA 2 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 cPLA 2 is observed, thus arguing for a cross-talk between the two classes of PLA 2. 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 sPLA 2-induced cPLA 2 activation, indicating that both kinases are essential for the cross-talk between the two types of PLA 2. The effect of sPLA 2 is mimicked by lysophosphatidylcholine (LPC), a reaction product of sPLA 2 activity. LPC stimulates PKC- ϵ, Raf-1 kinase and MAPK activation as well as cPLA 2 activation with a subsequent increase in arachidonic acid release from mesangial cells. These data suggest that sPLA 2 by cleaving membrane phospholipids and generating LPC and other lysophospholipids activates cPLA 2 via the PKC/Raf-1/MAPK signalling pathway. Hence a network of interactions between different PLA 2s is operative in mesangial cells and may contribute to the progression of glomerular inflammatory processes.