Oxidized phospholipids induce changes in hepatic paraoxonase and ApoJ but not monocyte chemoattractant protein-1 via interleukin-6.
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.
Van Lenten
B J
BJ
Division of Cardiology, Department of Medicine, UCLA School of Medicine, Los Angeles, California 90095-1679, USA. bvanlent@mednet.ucla.edu
Wagner
A C
AC
Navab
M
M
Fogelman
A M
AM
D000818:Animals; D043303:Aryldialkylphosphatase; D001483:Base Sequence; D018932:Chemokine CCL2 / Q000378:metabolism*; D051152:Clusterin; D017931:DNA Primers; D004950:Esterases / Q000378:metabolism*; D005260:Female; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism*; D008099:Liver / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D010743:Phospholipids / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics
D018932:Chemokine CCL2; C495243:Clu protein, mouse; D051152:Clusterin; D017931:DNA Primers; D006023:Glycoproteins; D015850:Interleukin-6; D018832:Molecular Chaperones; D010743:Phospholipids; D012333:RNA, Messenger; D004950:Esterases; D043303:Aryldialkylphosphatase