© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
8-Isoprostane increases expression of interleukin-8 in human macrophages through activation of mitogen-activated protein kinases
aResearch Institute for Internal Medicine, The National Hospital, University of Oslo, Sognsvannsveien 20, N-0027 Oslo, Norway
bSection of Clinical Immunology and Infectious Diseases, Medical Department, The National Hospital, University of Oslo, N-0027 Oslo, Norway
cDepartment of Cardiology, Medical Department, The National Hospital, University of Oslo, N-0027 Oslo, Norway
dDepartment of Preventive Cardiology, Ullevål University Hospital, University of Oslo, Oslo, Norway
hanne.schulz{at}klinmed.uio.no
* Corresponding author. Tel.: +47-2-307-2787; fax: +47-2-307-3630.
Background and objectives: 8-Isoprostane is a marker of oxidative stress in vivo and increased plasma and urine levels are found in patients with vascular disease and in atherosclerotic plaques. Inflammatory chemokines such as interleukin (IL)-8 seem to play an important pathogenic role in atherogenesis. We therefore investigated the effects of 8-isoprostane on the expression of inflammatory chemokines with consciousness on IL-8 (mRNA and protein) in human macrophages. In addition, we studied the involvement of mitogen-activated protein kinases (ERK 1/2 and p38 MAPK) and nuclear factor-
B (NF-B) in this process. Methods and results: 8-Isoprostane (10 µM) induced IL-8 expression (mRNA and protein), measured by real-time quantitative RT-PCR and enzyme immunoassay, respectively, in both THP-1 macrophages and human monocyte-derived macrophages. Moreover, 8-isoprostane increased mRNA expression of macrophage inflammatory protein-1
as determined by RNase protection assay. In this process, 8-isoprostane induced the activation of two major MAP-kinases; ERK 1/2 and p38 MAPK. Furthermore, the ERK 1/2 inhibitor, PD98059, and the p38 MAPK inhibitor, SB203580, markedly reduced 8-isoprostane-induced IL-8 expression (mRNA and protein), while inhibition of NF-B activation and translocation had no significant effect on IL-8 expression. Conclusions: We show that 8-isoprostane increases IL-8 expression in human macrophages involving both ERK 1/2 and p38 MAPK, but not NF-B signaling pathway. These findings further support a link between oxidative stress/lipid peroxidation and inflammation in human macrophages and suggest a role for 8-isoprostane in this process. This 8-isoprostane-induced chemokine expression might be involved in the pathogenesis of atherosclerosis as well as other inflammatory disorders.
KEYWORDS Atherosclerosis; Free radicals; Inflammation; Macrophages; Protein kinases
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