Potentiation of Tumor Necrosis Factor α-induced Secreted Phospholipase A2 (sPLA2)-IIA Expression in Mesangial Cells by an Autocrine Loop Involving sPLA2 and Peroxisome Proliferator-activated Receptor α Activation

Sabine Beck,Gérard Lambeau,Kristen Scholz-Pedretti,Michael H Gelb,Marcel J.W Janssen,Suzanne H Edwards,David C Wilton,Josef Pfeilschifter,Marietta Kaszkin

doi:10.1074/jbc.m211763200

Abstract

In rat mesangial cells, exogenously added secreted phospholipases A2 (sPLA2s) potentiate the expression of pro-inflammatory sPLA2-IIA first induced by cytokines like tumor necrosis factor-alpha (TNFalpha) and interleukin-1 beta. The transcriptional pathway mediating this effect is, however, unknown. Because products of PLA2 activity are endogenous activators of peroxisome proliferator-activated receptor alpha (PPAR alpha, we postulated that sPLA2s mediate their effects on sPLA2-IIA expression via sPLA2 activity and subsequent PPAR alpha activation. This study shows that various sPLA2s, including venom enzymes, human sPLA2-IIA, and wild-type and catalytically inactive H48Q mutant of porcine pancreatic sPLA2-IB, enhance the TNF alpha-induced sPLA2-IIA expression at the mRNA and protein levels. In cells transfected with luciferase sPLA2-IIA promoter constructs, sPLA2s are active only when the promoter contains a functional PPRE-1 site. The effect of exogenous sPLA2s is also blocked by the PPAR alpha inhibitor MK886. Interestingly, the expression of sPLA2-IIA induced by TNF alpha alone is also attenuated by MK886, by the sPLA2-IIA inhibitor LY311727, by heparinase, which prevents the binding of sPLA2-IIA to heparan sulfate proteoglycans, and by the specific cPLA2-alpha inhibitor pyrrolidine-1. Together, these data indicate that sPLA2-IIA released from mesangial cells by TNF alpha stimulates its own expression via an autocrine loop involving cPLA2 and PPAR alpha. This signaling pathway is also used by exogenously added sPLA2s including pancreatic sPLA2-IB and is distinct from that used by TNF alpha.

Highlights

In rat mesangial cells, exogenously added secreted phospholipases A2 potentiate the expression of pro-inflammatory sPLA2-IIA first induced by cytokines like tumor necrosis factor-␣ (TNF␣) and interleukin-1␤
This paper shows that various sPLA2s, when added exogenously to rat mesangial cells, can dramatically up-regulate the expression of sPLA2-IIA induced by the potent proinflammatory cytokines such as TNF␣
This paper shows that the endogenous rat sPLA2-IIA initially induced by TNF␣ can enhance its own expression through an autocrine loop

Summary

Introduction

Exogenously added secreted phospholipases A2 (sPLA2s) potentiate the expression of pro-inflammatory sPLA2-IIA first induced by cytokines like tumor necrosis factor-␣ (TNF␣) and interleukin-1␤. Exogenous sPLA2-IIA and lysophospholipids were found to rapidly stimulate the mitogen activated protein kinase cascade in mesangial cells, leading to early activation of cPLA2 [13, 14] It is, unclear whether sPLA2-IIA released by mesangial cells after cytokine induction acts like exogenously added sPLA2-IIA and, in particular, whether sPLA2-IIA can exert a positive feedback amplification loop on its own gene expression by activating one of the above signaling pathways and/or other pathways (see below). Unclear whether sPLA2-IIA released by mesangial cells after cytokine induction acts like exogenously added sPLA2-IIA and, in particular, whether sPLA2-IIA can exert a positive feedback amplification loop on its own gene expression by activating one of the above signaling pathways and/or other pathways (see below) High levels of another sPLA2 subtype, the so-called pancreatic-type sPLA2-IB, are found in kidney during acute pancreatitis [7, 15], suggesting that sPLA2-IB may contribute to the pathophysiological effects in such conditions. Goethe-Universitat, Theodor-Stern-Kai PPRE, peroxisome proliferator-responsive element; kbp, kilobase

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