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

Incubation of rat glomerular mesangial cells with potent proinflammatory cytokines like interleukin 1 beta (IL-I beta) 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 delta and epsilon and of p42 mitogen-activated protein kinase (MAPK), two putative activators of cytosolic phospholipase A(2) (cPLA(2)). sPLA(2) also activates Raf-l 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-epsilon, Raf-l 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(2)s is operative in mesangial cells and may contribute to the progression of glomerular inflammatory processes. (C) 1997 Elsevier Science B.V.