Oxidized Phospholipids Induce Changes in Hepatic Paraoxonase and ApoJ but Not Monocyte Chemoattractant Protein-1 via Interleukin-6

Brian J Van Lenten,Alan C Wagner,Mohamad Navab,Alan M Fogelman

doi:10.1074/jbc.m004074200

Brian J Van Lenten, Alan C Wagner + Show 2 more

Open Access

https://doi.org/10.1074/jbc.m004074200

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Abstract

In this study, we tested if interleukin-6 (IL-6) plays a role in mediating the effects of oxidized phospholipids (OXPL). Treatment of HepG2 cells with oxidized 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphoryl choline (OX-PAPC), or biologically active lipids present in mildly oxidized low density lipoprotein, increased apolipoprotein J (apoJ), and decreased paraoxonase (PON) mRNA levels. Antibodies to IL-6 blocked these changes. IL-6 treatment in the absence of OXPL produced the same pattern of mRNA changes observed with OXPL treatment alone. In vivo, OX-PAPC injected into C57BL/6J mice resulted in a marked reduction in PON activity and an increase in apoJ levels in plasma after 16 h. Injection of OX-PAPC into IL-6-deficient C57BL/6J mice (IL-6 -/-) did not alter either PON activity or apoJ levels. We then tested if other mechanisms involved in fatty streak formation depended upon IL-6. Antibody to IL-6 had no effect on OX-PAPC-induced secretion of MCP-1 by endothelial cells nor on MCP-1 mRNA expression in HepG2 cells. C57BL/6J and IL-6 -/- mice fed an atherogenic diet both demonstrated markedly reduced plasma PON activities and the IL-6 -/- mice developed fatty streaks to a greater degree than wild-type mice. We conclude that IL-6 is critical to short term but not long term regulation of PON and that IL-6 is not required for OXPL regulation of MCP-1.

Highlights

In this study, we tested if interleukin-6 (IL-6) plays a role in mediating the effects of oxidized phospholipids (OXPL)
HepG2 cells incubated for 16 h in medium alone or in medium containing 100 ␮g/ml nonoxidized phospholipid PAPC showed no differences with respect to the levels of expression of PON mRNA (Fig. 1)
HepG2 cells were incubated in medium alone, or in medium containing a dose of recombinant IL-6 shown to be active in vitro (100 ng/ml) [11] for 16 h and mRNA levels for PON and apolipoprotein J (apoJ) measured

Summary

Introduction

We tested if interleukin-6 (IL-6) plays a role in mediating the effects of oxidized phospholipids (OXPL). OX-PAPC injected into C57BL/6J mice resulted in a marked reduction in PON activity and an increase in apoJ levels in plasma after 16 h.

Results

Conclusion