Cross‐talk between group IIA‐phospholipase A₂ and inducible NO‐synthase in rat renal mesangial cells

Abstract

1 Features of glomerulonephritis are expression of the inducible form of NO synthase (iNOS) as well as expression of the secretory group IIA-phospholipase A 2 (sPLA 2 ) in mesangial cells. Interleukin 1b (IL-1b) induces both enzymes with a similar time course resulting in an increase in nitrite production and sPLA 2 -IIA activity. In this study we investigated the relationship between the formation of NO and sPLA 2 -IIA induction in rat renal mesangial cells. 2 Incubation of mesangial cells with the NO-donor, spermine-NONOate, for 24 h induced sPLA 2 -IIA mRNA expression and activity, whereas S-nitroso glutathione alone had only a small stimulatory e ect. Stimulation of cells with IL-1b caused a marked increase in sPLA 2 -IIA mRNA and activity that were potentiated 3 fold by both NO donors. 3 Coincubation of cells with IL-1b and the NOS inhibitor, L-N G monomethylarginine (L-NMMA), caused a dose-dependent inhibition of cytokine-induced sPLA 2 -IIA mRNA expression and activity. 4 sPLA 2 -IIA activity was not stimulated by 8-bromo-cyclic GMP indicating that NO-induced sPLA 2 -IIA induction is independent of cyclic GMP-mediated signal transduction. 5 These data show that NO contributes to the expression by cytokines of sPLA 2 -IIA and establishes a novel type of interaction between iNOS and sPLA 2 -IIA in mesangial cells. This cross-talk between in¯ammatory mediators may help to promote and sustain an in¯ammatory state in the kidney.

Inhibition of NFκB‐mediated pro‐inflammatory gene expression in rat mesangial cells by the enolized 1,3‐dioxane‐4,6‐dione‐5‐carboxamide, CGP‐43182

“…Recently, we have obtained evidence that group IIA sPLA 2 gene expression in mesangial cells is strongly dependent on NO formation by iNOS (Rupprecht et al, 1999). Similarly, Cox-2 mRNA expression and enzyme activity are stimulated by NO in mesangial cells (Salvemini, 1997).…”

“…Recently we described that the IL1b-stimulated gene expression of group IIA sPLA 2 is strongly dependent on NO produced by iNOS in mesangial cells (Rupprecht et al, 1999). Since group IIA sPLA 2 and Cox-2 were inhibited at the transcriptional level by CGP-43182, we hypothesized that the induction of iNOS in mesangial cells might also be aected by this compound.…”

“…Recently, we and others have shown that the gene expression of group IIA sPLA 2 and cyclo-oxygenase 2 (Cox-2) in mesangial cells is strongly dependent on endogenous NO formed by the action of the inducible nitric oxide synthase (iNOS) (Rupprecht et al, 1999;Salvemini, 1997). This enzyme, in turn, is regulated at the transcriptional level by cytokines (Eberhardt et al, 1998).…”

“…This enzyme, in turn, is regulated at the transcriptional level by cytokines (Eberhardt et al, 1998). An inhibition of IL1b-stimulated iNOS activity and NO formation results in a nearly complete inhibition of group IIA sPLA 2 mRNA expression (Rupprecht et al, 1999).…”

Secretory Phospholipase A2-Potentiated Inducible Nitric Oxide Synthase Expression by Macrophages Requires NF-κB Activation

“…It has also been reported that sPLA 2 enhances the response of leukocytes to LPS, which suggests a direct interaction of sPLA 2 with LPS (34). Rupprecht et al have shown and suggested cross talk between sPLA 2 and iNOS in rat renal mesangial cells (35). Recently, Tsukahara et al reported that the PLA 2 inhibitor quinacrine inhibited iNOS expression in alveolar macrophages and reduced lung injury in acute pancreatitis.…”