Low-density lipoprotein modified by macrophage-derived lysosomal hydrolases induces expression and secretion of IL-8 via p38 MAPK and NF-kappaB by human monocyte-derived macrophages.
OBJECTIVE
Modified lipoproteins induce inflammatory reactions in the atherosclerotic arterial wall. We have previously found that macrophages in atherosclerotic lesions secrete lysosomal hydrolases that can modify low-density-lipoprotein (LDL) in vitro to generate "hydrolase-modified LDL" (H-LDL). Here, we studied whether H-LDL exerts inflammatory effects on cultured human macrophages.


RESULTS
Using cytokine cDNA arrays, we found that H-LDL induced expression of IL-8, but not of the anti-inflammatory cytokines IL-10 and transforming growth factor (TGF)-beta, in human monocyte-derived macrophages. H-LDL induced rapid phosphorylation of the p38 mitogen-activated protein kinase (MAPK), nuclear translocation of 2 transcription factors, nuclear factor kappaB (NF-kappaB) and activator protein 1 (AP-1), and time-dependent secretion of IL-8 from the macrophages. Inhibition of MAPKs and of transcription factors showed that p38 MAPK and NF-kappaB, but not ERK1/2, JNK, or AP-1, were crucial for the H-LDL-induced IL-8 secretion from the macrophages.


CONCLUSIONS
The results show that by activating p38 MAPK and NF-kappaB, macrophage hydrolases modify LDL into biologically active particles capable of triggering the secretion of IL-8 in macrophages. Thus, activated hydrolase-secreting macrophages in atherosclerotic lesions may sustain a proatherogenic extracellular environment by hydrolyzing LDL and triggering it to act in an autocrine or paracrine fashion to induce IL-8 secretion by the plaque macrophages.
Hakala
Jukka K
JK
Wihuri Research Institute, Kalliolinnantie 4, FIN-00140 Helsinki, Finland.
Lindstedt
Ken A
KA
Kovanen
Petri T
PT
Pentikäinen
Markku O
MO
D001692:Biological Transport; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D004789:Enzyme Activation; D006801:Humans; D006867:Hydrolases / Q000378:metabolism*; D007249:Inflammation / Q000209:etiology; D016209:Interleukin-8 / Q000378:metabolism*; D008077:Lipoproteins, LDL; D008247:Lysosomes / Q000201:enzymology*; D008264:Macrophages / Q000201:enzymology / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D016209:Interleukin-8; D008077:Lipoproteins, LDL; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D048051:p38 Mitogen-Activated Protein Kinases; D006867:Hydrolases