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(Stroke. 2003;34:1864.)
© 2003 American Heart Association, Inc.

Original Contributions

Multiple Levels of Regulation of the Interleukin-6 System in Stroke

Daniela Acalovschi; Tina Wiest, PhD; Marius Hartmann, MD; Maryam Farahmi; Ulrich Mansmann, PhD; Gerd U. Auffarth, MD; Armin J. Grau, MD; Fiona R. Green, PhD; Caspar Grond-Ginsbach, PhD Markus Schwaninger, MD

From the Departments of Neurology (D.A., T.W., M.H., M.F., A.J.G., C.G.G., M.S.), Ophthalmology (G.U.A.), and Biometry (U.M.), University of Heidelberg, Heidelberg, Germany; BHF Molecular Cardiology Laboratory, Department of Cardiovascular Medicine, University of Oxford, Wellcome Trust Centre for Human Genetics (F.G.), Oxford, UK; Department of Neurology, University of Cluj-Napoca, Cluj-Napoca, Romania (D.A.).

Correspondence to Markus Schwaninger, MD, PhD, Department of Neurology, University of Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany. E-mail markus.schwaninger{at}med.uni-heidelberg.de

Background and Purpose— Serum levels of the cytokine interleukin-6 (IL-6) rise markedly in stroke. IL-6 is a key regulator of inflammatory mechanisms that play an important part in stroke pathophysiology. The action of IL-6 is modified by its soluble receptor subunits sgp130 and sIL-6R. The purpose of this study was to investigate whether serum levels of the receptor subunits are changed after ischemic stroke and to define the role of genetic influences on IL-6 expression in acute stroke.

Methods— In 48 patients with acute stroke and 48 age- and sex-matched control subjects, serum concentrations of IL-6, sgp130, and sIL-6R were measured by enzyme-linked immunosorbent assay. Furthermore, IL-6 promoter haplotypes comprising 4 different polymorphisms (-597GA, -572GC, -373A(n)T(n), -174GC) were determined by DNA sequencing and allele-specific oligonucleotide polymerase chain reaction. The effect of the common haplotypes on IL-6 gene transcription was tested by transfecting reporter fusion genes in the astrocytelike cell line U373.

Results— Whereas serum concentrations of IL-6 significantly rose (P<0.001), sgp130 levels were transiently reduced after stroke (P<0.05), and sIL-6R levels remained unchanged. IL-6 levels depended on the infarct size and the haplotype of the promoter region. The common haplotype A-G-8/12-C was associated with low IL-6 levels after stroke and a reduced induction of IL-6 transcription on stimulation with an adenosine analog in vitro.

Conclusions— The data demonstrate genetic variation in the expression of IL-6 in stroke. Induction of the inflammatory response by IL-6 might be enhanced by a transient downregulation of the potential IL-6 antagonist sgp130.

Key Words: acute-phase reaction • interleukins • polymorphism

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