STIMULATION OF INTERLEUKIN-6 SECRETION AND GENE-TRANSCRIPTION IN PRIMARY ASTROCYTES BY ADENOSINE

During cerebral ischemia, the expression of interleukin-6 (IL-6), whic h has neuroprotective properties, increases, To understand the underly ing mechanism, the regulation of IL-6 expression by neurotransmitters that accumulate during cerebral ischemia was investigated, Adenosine s timulated IL-6 secretion in primary astrocytes four-to 10-fold, The ef fect was concentration dependent, the EC50 being similar to 8 mu M. Al though the nonselective analogue 2-chloroadenosine (2CA) increased IL- 6 secretion to a similar extent, the A(1)-selective agonist N-6-cyclop entyladenosine or the A(2a) agonist CGS-21680 had only a marginal effe ct on IL-6 secretion. IL-6 secretion stimulated by 2CA (10 mu M) was i nhibited by the nonselective adenosine antagonist 8-(p-sulfophenyl)the ophylline, whereas the A(1)-selective antagonist 8-cyclopentyl-1,3-dip ropylxanthine or the A(2a)-selective antagonist 8-(3-chlorostyryl)caff eine had no effect, to a concentration of 0.1 mu M. Transcription of t he 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 bind ing site for NF-kappa B or NF-IL6 abrogated the response to 2CA, Thus, an increase of extracellular adenosine during focal cerebral ischemia may stimulate IL-6 expression via A(2b) receptors. The induction of I L-6 expression appears to involve a transcriptional effect that depend s on NF-kappa B and NF-IL6.