Multiple levels of regulation of the interleukin-6 system in stroke.
OBJECTIVE
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 (-597G-->A, -572G-->C, -373A(n)T(n), -174G-->C) 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.
Acalovschi
Daniela
D
Department of Neurology, University of Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany.
Wiest
Tina
T
Hartmann
Marius
M
Farahmi
Maryam
M
Mansmann
Ulrich
U
Auffarth
Gerd U
GU
Grau
Armin J
AJ
Green
Fiona R
FR
Grond-Ginsbach
Caspar
C
Schwaninger
Markus
M
D000208:Acute Disease; D015703:Antigens, CD / Q000097:blood; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000032:analysis; D002460:Cell Line; D050822:Cytokine Receptor gp130; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005787:Gene Frequency; D017930:Genes, Reporter; D006239:Haplotypes; D006801:Humans; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000097:blood; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D011446:Prospective Studies; D019947:Receptors, Interleukin-6 / Q000097:blood; D020521:Stroke / Q000097:blood / Q000378:metabolism*; D014162:Transfection
D015703:Antigens, CD; D015415:Biomarkers; C494199:IL6ST protein, human; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D019947:Receptors, Interleukin-6; D050822:Cytokine Receptor gp130; D002097:C-Reactive Protein