CLINICAL STUDY
Enhanced gene expression of chemokines and their corresponding receptors in mononuclear blood cells in chronic heart failure—modulatory effect of intravenous immunoglobulin
Jan K. Damås, MD*  ,
Lars Gullestad, MD, PhD*,
Halfdan Aass, MD, PhD*,
Svein Simonsen, MD, PhD*,
Jan G. Fjeld, MD, PhD ,
Lisbeth Wikeby, RN* ,
Thor Ueland, BS  ,
Hans G. Eiken, PhD ¶,
Stig S. Frøland, MD, PhD || and
P.ål Aukrust, MD, PhD ||
* Department of Cardiology, Medical Department, University of Oslo, The National Hospital, Oslo, Norway
Research Institute for Internal Medicine, Medical Department, University of Oslo, The National Hospital, Oslo, Norway
Section of Nuclear Medicine, Medical Department, University of Oslo, The National Hospital, Oslo, Norway
Section of Endocrinology, Medical Department, University of Oslo, The National Hospital, Oslo, Norway
¶ MSD-Cardiovascular Research Center, Medical Department, University of Oslo, The National Hospital, Oslo, Norway
|| Section of Clinical Immunology and Infectious Diseases, Medical Department, University of Oslo, The National Hospital, Oslo, Norway
Manuscript received November 21, 2000;
revised manuscript received March 13, 2001,
accepted March 26, 2001.
Reprint requests and correspondence: Dr. Jan K. Damås, Research Institute for Internal Medicine, Rikshospitalet, N-0027 Oslo, Norway
j.k.damas{at}klinmed.uio.no
OBJECTIVES
We sought to study the gene expression of chemokines and their corresponding receptors in mononuclear blood cells (MNCs) from patients with chronic heart failure (CHF), both of which were cross-sectional and longitudinal studies during therapy with intravenous immunoglobulin (IVIg).
BACKGROUND
We have recently demonstrated that IVIg improves left ventricular ejection fraction (LVEF) in patients with CHF. Based on the potential pathogenic role of chemokines in CHF, we hypothesized that the beneficial effect of IVIg may be related to a modulatory effect on the expression of chemokines and their receptors in MNCs.
METHODS
We examined: 1) the gene expression of C, CC and CXC chemokines and their receptors in MNCs from 20 patients with CHF and 10 healthy blood donors; and 2) the expression of these genes in MNCs from 20 patients with CHF randomized in a double-blind fashion to therapy with IVIg or placebo for 26 weeks.
RESULTS
Our main findings in CHF were: 1) markedly raised gene expression of macrophage inflammatory protein (MIP)-1 , MIP-1ß and interleukin (IL)-8; 2) enhanced gene expression of their corresponding receptors; 3) modulation in a normal direction of this abnormal chemokine and chemokine receptor gene expression during IVIg, but not during placebo therapy; 4) down-regulation of MIP-1, MIP-1ß and IL-8 during IVIg at the protein level in plasma; and 5) a correlation between down-regulation of MIP-1 gene expression and improved LVEF during IVIg therapy.
CONCLUSIONS
Our results further support a pathogenic role for chemokines in CHF and suggest that IVIg may represent a novel therapeutic approach, with the potential to improve LVEF in patients with CHF, possibly by modulatory effects on the chemokine network.
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Abbreviations and Acronyms
| | CCR | = CC chemokine receptor | | CHF | = chronic heart failure | | CXCR | = CXC chemokine receptor | | IL-8 | = interleukin-8 | | IVIg | = intravenous immunoglobulin | | LVEF | = left ventricular ejection fraction | | MIP-1 or -1ß | = macrophage inflammatory protein-1 or -1ß | | MNCs | = mononuclear blood cells | | (m)RNA | = (messenger) ribonucleic acid | | RPA | = ribonuclease protection assay |
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