Statins potentiate the IFN-γ-induced upregulation of group IIA phospholipase A 2 in human aortic smooth muscle cells and HepG2 hepatoma cells

Abstract

The present study shows that the incubation of human aortic smooth muscle cells (HASMC) and HepG2 cells with atorvastatin and mevastatin as HMG-CoA reductase inhibitors potentiated the interferon-γ (INF-γ)-induced group IIA phospholipase A 2 (sPLA 2-IIA) expression in a dose- and time-dependent manner. The effect of statins on sPLA 2-IIA expression was reduced by mevalonate, farnesyl pyrophosphate and geranylgeranyl pyrophosphate. Inversely, inhibitors of the farnesyl transferase and geranylgeranyl transferase-I mimicked the effects of statins. Clostridium difficile toxin B (TcdB), Y-27632 and H-1152, functioning as inhibitors of Rho proteins and Rho-associated kinase, also augmented the sPLA 2-IIA expression in combination with IFN-γ. The same effects were observed when inhibitors of mitogen-activated/extracellular response protein kinase kinase (MEK), PD98059 or U0126 were used. Further, the Janus kinase-2 (Jak2)-specific inhibitor, AG-490 and inhibitors of nuclear factor-κB (NFκB) abrogated the sPLA 2-IIA elevating effects of statins, TcdB and PD98059 in the presence of IFN-γ. This cytokine alone increased the NFκB p65 and CAAT-enhancer-binding protein-β (C/EBP-β) activity in HASMC nuclear extract, but only C/EBP-β was further augmented when the cells were incubated in addition to IFN-γ with atorvastatin, H-1152, PD98059 or U0126. Moreover, after the incubation of cells with atorvastatin and IFN-γ the stability of sPLA- 2IIA mRNA significantly increased in comparison to those after incubation with IFN-γ alone. In conclusion, the obtained data suggest that (i) the expression of sPLA 2-IIA is negatively regulated by RhoA/Rho-associated kinase and MEK/ERK signaling pathways and (ii) statins, because of their ability to down-regulate these pathways, can potentiate the IFN-γ-induced sPLA 2-II expression at transcriptional and post-transcriptional levels.