Adenosine-induced expression of interleukin-6 in astrocytes through protein kinase A and NF-IL-6

✍ Scribed by Markus Schwaninger; Nicole Petersen; Simone Prinz; Svea Sallmann; Mike Neher; Matthias Spranger

• Publisher: John Wiley and Sons
• Year: 2000
• Tongue: English
• Weight: 179 KB
• Volume: 31
• Category: Article
• ISSN: 0894-1491
• DOI: 10.1002/(sici)1098-1136(200007)31:1<51::aid-glia50>3.0.co;2-m

✦ Synopsis

In various neurologic diseases, astrocytes express interleukin-6 (IL-6), which is an endogenous pyrogen, a neuroprotective factor, and a regulator of the blood-brain barrier. The expression of IL-6 in astrocytes is stimulated by extracellular adenosine through A 2B receptors. To investigate the signaling cascade that induces IL-6 gene transcription further, we transfected primary mouse astrocytes with a reporter gene construct, in which luciferase expression is directed by the human IL-6 promoter. Expression of PKI, an inhibitor of protein kinase A (PKA), interfered with IL-6 transcription indicating that PKA mediates the effect of adenosine. The CAAT box of the IL-6 promoter is necessary for the stimulation by adenosine as a mutation in this element reduced the stimulation by adenosine. Indeed, the cAMP agonist forskolin increased the binding of the transcription factors NF-IL-6 and C/EBP␦ to the CAAT box of the IL-6 promoter in nuclear extracts of astrocytes. Inhibition of the de novo synthesis of NF-IL-6 by cycloheximide or an antisense oligonucleotide reduced the enhancement of NF-IL-6 binding to the CAAT box and inhibited stimulation of IL-6 transcription by forskolin. In addition, overexpression of NF-IL-6 induced IL-6 transcription. This suggests that adenosine induces the de novo synthesis of NF-IL-6 through activation of PKA and thereby stimulates transcription of IL-6 in astrocytes. GLIA 31:51-58, 2000.