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 ∼8 µM. Although the nonselective analogue 2‐chloroadenosine (2CA) increased IL‐6 secretion to a similar extent, the A₁‐selective agonist N⁶‐cyclopentyladenosine or the A_2a agonist CGS‐21680 had only a marginal effect on IL‐6 secretion. IL‐6 secretion stimulated by 2CA (10 µM) was inhibited by the nonselective adenosine antagonist 8‐(p‐sulfophenyl)theophylline, whereas the A₁‐selective antagonist 8‐cyclopentyl‐1,3‐dipropylxanthine or the A_2a‐selective antagonist 8‐(3‐chlorostyryl)caffeine had no effect, to a concentration of 0.1 µM. 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‐κB 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 IL‐6 expression appears to involve a transcriptional effect that depends on NF‐κB and NF‐IL6.