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Papers In Press, published online ahead of print October 8, 2001
Department of Medicine, University of Chicago, Chicago, IL 60637
Corresponding Author: ascanu{at}medicine.bsd.uchicago.edu
In the vessel wall, macrophages are among the cells that upon activation contribute to the atherosclerotic process. Low density lipoproteins (LDL) can mediate this activation but only after enzymatic or oxidative modification. Lipoprotein(a), (Lp(a)), is an LDL variant that has been shown to have an atherogenic potential by no clearly established mechanisms. In the present study we examined whether native Lp(a) can activate macrophages and, if so, identify the structural elements involved in this action. For this purpose, we utilized human THP-1 macrophages, prepared by treating THP-1 monocytes with phorbol ester and exposed them to Lp(a) and its two derivatives: apo(a)-free LDL (Lp(a-)) and free apo(a). We also studied apo(a) fragments, F1(N-terminal) and F2 (C-terminal) and sub-fragments thereof, obtained by leukocyte elastase digestion. By Northern blot analyses, Lp(a), but not Lp(a-), caused up to 12-fold increase in interleukin 8 (IL-8) mRNA as compared to untreated cells. Free apo(a) also induced the production of IL-8 mRNA; however, the effect was 3-4 fold higher than that of Lp(a). The increase in mRNA was associated with the accumulation of IL-8 protein in the culture medium. F1 had only a minimal effect whereas F2 was 1.5-2 fold more potent than apo(a), an activity mostly contained in the KV-protease region. A monoclonal antibody specific for KV, inhibited the apo(a)-mediated effect on IL-8. We conclude that Lp(a) via elements contained in the C-terminal domain of apo(a), causes in THP-1 macrophages an increased production of IL-8, a chemokine with pro-inflammatory properties, an event that may be relevant to the process of atherosclerosis.
J. Biol. Chem, 10.1074/jbc.M107943200
Submitted on August 17, 2001
Revised on October 8, 2001
Accepted on October 8, 2001
Stimulation of interleukin-8 production in human THP-1 macrophages by apolipoprotein (a): evidence for a critical involvement of elements in its C-terminal domain
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