Interleukin-6 (IL-6) Production by Astrocytes: Autocrine Regulation by IL-6 and the Soluble IL-6 Receptor

In the CNS, astrocytes are a major inducible source of interleukin-6 (IL-6). Although IL-6 has beneficial effects in the CNS because of its neurotrophic properties, its overexpression is generally detrimental, adding to the pathophysiology associated with CNS disorders. Many factors have been shown...

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Bibliographic Details
Published in:The Journal of neuroscience 1999-07, Vol.19 (13), p.5236-5244
Main Authors: Van Wagoner, Nicholas J, Oh, Jae-Wook, Repovic, Pavle, Benveniste, Etty N
Format: Article
Language:English
Subjects:
Astrocytes - cytology
Astrocytes - drug effects
Astrocytes - metabolism
Autocrine Communication - drug effects
Cell Line
Cells, Cultured
Drug Synergism
Gene Expression Regulation - drug effects
Half-Life
Humans
Interleukin-1 - pharmacology
Interleukin-6 - biosynthesis
Interleukin-6 - genetics
Interleukin-6 - pharmacology
Interleukin-6 - physiology
Oncostatin M
Peptides - pharmacology
Receptors, Interleukin-6 - physiology
RNA, Messenger - biosynthesis
RNA, Messenger - genetics
RNA, Messenger - metabolism
Solubility
Transcription, Genetic - drug effects
Transforming Growth Factor beta - pharmacology
Tumor Necrosis Factor-alpha - pharmacology
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Summary:In the CNS, astrocytes are a major inducible source of interleukin-6 (IL-6). Although IL-6 has beneficial effects in the CNS because of its neurotrophic properties, its overexpression is generally detrimental, adding to the pathophysiology associated with CNS disorders. Many factors have been shown to induce IL-6 expression by astrocytes, particularly the cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1beta). However, the role of IL-6 in its own regulation in astrocytes has not been determined. In this study, we examined the influence of IL-6 alone or in combination with TNF-alpha or IL-1beta on IL-6 expression. IL-6 alone had no effect on IL-6 expression; however, the addition of the soluble IL-6 receptor (sIL-6R) induced IL-6 transcripts. Addition of TNF-alpha or IL-1beta plus IL-6/sIL-6R led to synergistic increases in IL-6 expression. This synergy also occurred in the absence of exogenously added IL-6, attributable to TNF-alpha- or IL-1beta-induced endogenous IL-6 protein production. IL-6 upregulation seen in the presence of TNF-alpha or IL-1beta plus IL-6/sIL-6R was transcriptional, based on nuclear run-on analysis. Experiments were extended to other IL-6 family members to determine their role in IL-6 regulation in astrocytes. Oncostatin M (OSM) induced IL-6 alone and synergized with TNF-alpha for enhanced expression. These results demonstrate that IL-6/sIL-6R and OSM play an important role in the regulation of IL-6 expression within the CNS, particularly in conjunction with the proinflammatory cytokines TNF-alpha and IL-1beta.
ISSN:0270-6474
1529-2401
DOI:10.1523/jneurosci.19-13-05236.1999