Combined anti-inflammatory effects of β2-adrenergic agonists and PDE4 inhibitors on astrocytes by upregulation of intracellular cAMP

Christiansen, Søren Hofman; Selige, Jens; Dunkern, Torsten; Rassov, Andreas; Leist, Marcel

Combined anti-inflammatory effects of β2-adrenergic agonists and PDE4 inhibitors on astrocytes by upregulation of intracellular cAMP

Dateien

Christiansen_181484.pdfGröße: 643.64 KBDownloads: 605

Datum

2011

Autor:innen

Christiansen, Søren Hofman

Selige, Jens

Dunkern, Torsten

Rassov, Andreas

Leist, Marcel

Open Access-Veröffentlichung

Open Access Green

Sammlungen

Biologie

Publikationstyp

Zeitschriftenartikel

Publikationsstatus

Published

Erschienen in

Neurochemistry International. 2011, 59(6), pp. 837-846. ISSN 0197-0186. eISSN 1872-9754. Available under: doi: 10.1016/j.neuint.2011.08.012

Zusammenfassung

Inflammation is an important hallmark of all neurodegenerative diseases and activation of different glial populations may be involved in the progression of some of these disorders. Especially, the activation of astroglia can lead to long-term detrimental morphological changes, such as scar formation. Therefore, improved strategies to modulate inflammation in these cells are currently being investigated. We investigated the interaction of phosphodiesterase (PDE) 4 inhibitors, such as rolipram, with other agents raising cellular cAMP levels. When used alone, none of the PDE4 inhibitors increased cAMP levels. The adenylate cyclase activator forskolin, the b2-adrenergic agonist clenbuterol and the mixed b1/b2-adrenergic agonist isoproterenol increased intracellular cAMP levels of cortical murine astrocytes. This increase was synergistically elevated by rolipram or the PDE4 inhibitor RO-201724, but not by inhibition of PDE3. Inflammatory stimulation of the cells with the cytokines TNF-a, IL-1b and IFN-c strongly induced PDE4B and augmented overall PDE4 activity, while PDE3 activity was low. Clenbuterol and forskolin caused downregulation of cytokines and chemokines such as IL-6 and MCP-1. This effect was further enhanced by rolipram, but not by the PDE3 inhibitor milrinone. The cAMP-raising drug combinations attenuated the upregulation of TNF-a and IL-6 mRNA and the secretion of IL-6, but did not affect initial NF-jB signalling triggered by the stimulating cytokines. These results indicate that PDE4 may be a valuable anti-inflammatory target in brain diseases, especially under conditions associated with stimulation of cAMP-augmenting astrocyte receptors as is observed by clenbuterol treatment.

Fachgebiet (DDC)

570 Biowissenschaften, Biologie

Schlagwörter

Astrocytes, Inflammation, cAMP, PDE4, b-Adrenoceptors

Zitieren

ISO 690

CHRISTIANSEN, Søren Hofman, Jens SELIGE, Torsten DUNKERN, Andreas RASSOV, Marcel LEIST, 2011. Combined anti-inflammatory effects of β2-adrenergic agonists and PDE4 inhibitors on astrocytes by upregulation of intracellular cAMP. In: Neurochemistry International. 2011, 59(6), pp. 837-846. ISSN 0197-0186. eISSN 1872-9754. Available under: doi: 10.1016/j.neuint.2011.08.012

BibTex

@article{Christiansen2011-11Combi-18148,
  year={2011},
  doi={10.1016/j.neuint.2011.08.012},
  title={Combined anti-inflammatory effects of β2-adrenergic agonists and PDE4 inhibitors on astrocytes by upregulation of intracellular cAMP},
  number={6},
  volume={59},
  issn={0197-0186},
  journal={Neurochemistry International},
  pages={837--846},
  author={Christiansen, Søren Hofman and Selige, Jens and Dunkern, Torsten and Rassov, Andreas and Leist, Marcel}
}

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Universitätsbibliographie

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