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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:2504.)
© 2006 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Low-Density Lipoprotein Modified by Macrophage-Derived Lysosomal Hydrolases Induces Expression and Secretion of IL-8 Via p38 MAPK and NF-B by Human Monocyte-Derived Macrophages

Jukka K. Hakala; Ken A. Lindstedt; Petri T. Kovanen; Markku O. Pentikäinen

From Wihuri Research Institute, Helsinki, Finland.

Correspondence to Petri T. Kovanen, Wihuri Research Institute, Kalliolinnantie 4, FIN-00140 Helsinki, Finland. E-mail Petri.Kovanen{at}wri.fi

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.

Methods and 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)-ß, 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 B (NF-B) 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-B, 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-B, 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.

LDL modified by secreted macrophage-derived lysosomal hydrolases (H-LDL) induce secretion of IL-8 by cultured human monocyte-derived macrophages. Secretion of IL-8 by H-LDL–stimulated macrophages depended on the activation of p38 MAPK and NF-B transcription factor.

Key Words: atherosclerosis • cytokines • inflammation • LDL