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Adenosine‐induced expression of interleukin‐6 in astrocytes through protein kinase A and NF‐IL‐6
Author(s) -
Schwaninger Markus,
Petersen Nicole,
Prinz Simone,
Sallmann Svea,
Neher Mike,
Spranger Matthias
Publication year - 2000
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/(sici)1098-1136(200007)31:1<51::aid-glia50>3.0.co;2-m
Subject(s) - biology , microbiology and biotechnology , forskolin , transcription factor , response element , ccaat enhancer binding proteins , creb , adenosine , cyclic amp response element binding protein , gene expression , promoter , stimulation , endocrinology , nuclear protein , biochemistry , gene
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/EBPδ 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. © 2000 Wiley‐Liss, Inc.