Cooperation of NFkappaB and CREB to induce synergistic IL-6 expression in astrocytes - PubMed (original) (raw)

Cooperation of NFkappaB and CREB to induce synergistic IL-6 expression in astrocytes

Anneleen Spooren et al. Cell Signal. 2010 May.

Erratum in

Abstract

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 NFkappaB in promoting the synergy was corroborated using IL-6 promoter point mutants, as well as via siRNA-mediated silencing of CREB and NFkappaB. Interestingly, whereas CREB and NFkappaB 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 NFkappaB-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.

2010 Elsevier Inc. All rights reserved.

PubMed Disclaimer

Similar articles

Cited by

Publication types

MeSH terms

Substances

LinkOut - more resources