Journal
CELLULAR SIGNALLING
Volume 22, Issue 5, Pages 871-881Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2010.01.018
Keywords
IL-6; NF kappa B; Neuroinflammation; CBP; beta-adrenergic receptors; CREB
Categories
Funding
- FWO Flanders
- Interuniversity Attraction Poles (IAP) [P6/18]
- GOA from Ghent University
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Astrocytes are critical players in the innate immune response of the central nervous system. Upon encountering proinflammatory stimuli, astrocytes produce a plethora of inflammatory mediators. Here, we have investigated how beta(2)-adrenergic receptor activation modulates proinflammatory gene expression in astrocytes. We have observed that treatment of human 1321N1 astrocytes with the beta-adrenergic agonist isoproterenol synergistically enhanced TNF-alpha-induced expression of the cytokine IL-6. The effect of isoproterenol was CAMP-dependent and mediated by the beta(2)-adrenergic subtype. Using pharmacological inhibitors and siRNA we showed that protein kinase A (PKA) is an indispensable mediator of the synergy. Simultaneous induction with isoproterenol and TNF-alpha was moreover associated with combined recruitment of CREB and p65 to the native IL-6 promoter. The role of CREB and NF kappa B in promoting the synergy was corroborated using IL-6 promoter point mutants, as well as via siRNA-mediated silencing of CREB and NF kappa B. Interestingly, whereas CREB and NF kappa B usually compete for the limiting cofactor CREB binding protein (CBP), we detected enhanced recruitment of CBP at the IL-6 promoter in our system. The transcriptional synergy seems to be a gene specific process, occurring at the IL-6 and COX-2 gene, but not at other typical NF kappa B-dependent genes such as IL-8, ICAM-1 or VCAM-1. As astrocytic IL-6 overexpression has been associated with neuroinflammatory and neurodegenerative processes, our findings might have important physiological consequences. (C) 2010 Elsevier Inc. All rights reserved.
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