Stimulation of interleukin-6 secretion and gene transcription in primary astrocytes by adenosine.
During cerebral ischemia, the expression of interleukin-6 (IL-6), which has neuroprotective properties, increases. To understand the underlying mechanism, the regulation of IL-6 expression by neurotransmitters that accumulate during cerebral ischemia was investigated. Adenosine stimulated IL-6 secretion in primary astrocytes four- to 10-fold. The effect was concentration dependent, the EC50 being approximately 8 microM. Although the nonselective analogue 2-chloroadenosine (2CA) increased IL-6 secretion to a similar extent, the A1-selective agonist N6-cyclopentyladenosine or the A2a agonist CGS-21680 had only a marginal effect on IL-6 secretion. IL-6 secretion stimulated by 2CA (10 microM) was inhibited by the nonselective adenosine antagonist 8-(p-sulfophenyl)theophylline, whereas the A1-selective antagonist 8-cyclopentyl-1,3-dipropylxanthine or the A2a-selective antagonist 8-(3-chlorostyryl)caffeine had no effect, to a concentration of 0.1 microM. Transcription of the IL-6 gene was investigated by transfecting primary astrocytes with a reporter fusion gene containing the human IL-6 promoter (-179/+12). 2CA stimulated IL-6 gene transcription 2.5-fold. Mutations of the binding site for NF-kappaB or NF-IL6 abrogated the response to 2CA. Thus, an increase of extracellular adenosine during focal cerebral ischemia may stimulate IL-6 expression via A2b receptors. The induction of IL-6 expression appears to involve a transcriptional effect that depends on NF-kappaB and NF-IL6.
Schwaninger
M
M
Department of Neurology, University of Heidelberg, Germany.
Neher
M
M
Viegas
E
E
Schneider
A
A
Spranger
M
M
D015762:2-Chloroadenosine / Q000494:pharmacology; D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D002540:Cerebral Cortex / Q000276:immunology / Q000378:metabolism*; D017930:Genes, Reporter; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D007700:Kinetics; D051379:Mice; D010627:Phenethylamines / Q000494:pharmacology; D058906:Purinergic P1 Receptor Agonists; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D014158:Transcription, Genetic
D015850:Interleukin-6; D010627:Phenethylamines; D058906:Purinergic P1 Receptor Agonists; D011993:Recombinant Fusion Proteins; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D015762:2-Chloroadenosine; C048599:N(6)-cyclopentyladenosine; D000241:Adenosine