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Originally published In Press as doi:10.1074/jbc.M107943200 on October 8, 2001

J. Biol. Chem., Vol. 276, Issue 50, 46864-46869, December 14, 2001
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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*

Olga KlezovitchDagger , Celina EdelsteinDagger , and Angelo M. ScanuDagger §

From the Departments of Dagger  Medicine and of § Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois 60637

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 we 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 terminus) and F2 (C terminus) and subfragments thereof, obtained by leukocyte elastase digestion. By Northern blot analyses, Lp(a), but not Lp(a-), caused up to a 12-fold increase in interleukin 8 (IL-8) mRNA as compared with 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 Kringle V-protease region. A monoclonal antibody specific for Kringle V 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.

* This work was supported by National Institutes of Health Grants HL18577 and HL63115.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Medicine, University of Chicago, 5841 S. Maryland Ave., MC5041, Chicago, IL 60637. Tel.: 773-702-1775; Fax: 773-702-4534; E-mail: ascanu@medicine.bsd.uchicago.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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Copyright © 2001 by the American Society for Biochemistry and Molecular Biology.