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Identification of early inflammatory genes involved in adenosine signaling using a pharmacogenomics approach


Paine, C. Identification of early inflammatory genes involved in adenosine signaling using a pharmacogenomics approach. 2009, University of Zurich, Vetsuisse Faculty.

Abstract

Adenosine is a paradoxical inflammatory modulator. It can both participate in inflammatory shutdown and also mediate the persistence of inflammation, by activating different adenosine receptors (AR). Here, a pharmacogenomics approach was employed to identify AR sub-type specific cellular signals in the human mast cell-line 1 (HMC-1). Two gene products previously not associated to adenosine signaling were further characterized. First, we determined that AR activation results in upreguation and secretion of macrophage inflammatory protein-1 beta (MIP-1β) into the cell culture medium, suggesting a mechanism by which adenosine can modulate chemotaxis by mast cells. Second, we detected a sharp upregulation of the inflammatory transcription factors NR4A2 and NR4A3, accompanied by an increase in their transcriptional activity. Notably, this effect appears to be mediated by A2BAR and A3AR, while A2AAR activation counteracted NR4A2 and NR4A3 induction by other ARs. Furthermore, while non-selective AR activation strongly potentiated PMA/I-mediated induction of NR4As, selective A2AAR engagement partially revoked it, indicating that A2AAR modulatory effect is conserved to other pro-inflammatory stimuli. Overall, these findings show that AR activation can have broad regulatory effects on human mast cells, not only by a direct effect on inflammation-associated factors, but also by influencing the recruitment of inflammatory cells through chemotactic cytokines.

Abstract

Adenosine is a paradoxical inflammatory modulator. It can both participate in inflammatory shutdown and also mediate the persistence of inflammation, by activating different adenosine receptors (AR). Here, a pharmacogenomics approach was employed to identify AR sub-type specific cellular signals in the human mast cell-line 1 (HMC-1). Two gene products previously not associated to adenosine signaling were further characterized. First, we determined that AR activation results in upreguation and secretion of macrophage inflammatory protein-1 beta (MIP-1β) into the cell culture medium, suggesting a mechanism by which adenosine can modulate chemotaxis by mast cells. Second, we detected a sharp upregulation of the inflammatory transcription factors NR4A2 and NR4A3, accompanied by an increase in their transcriptional activity. Notably, this effect appears to be mediated by A2BAR and A3AR, while A2AAR activation counteracted NR4A2 and NR4A3 induction by other ARs. Furthermore, while non-selective AR activation strongly potentiated PMA/I-mediated induction of NR4As, selective A2AAR engagement partially revoked it, indicating that A2AAR modulatory effect is conserved to other pro-inflammatory stimuli. Overall, these findings show that AR activation can have broad regulatory effects on human mast cells, not only by a direct effect on inflammation-associated factors, but also by influencing the recruitment of inflammatory cells through chemotactic cytokines.

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Additional indexing

Item Type:Dissertation
Referees:Althaus F R
Communities & Collections:05 Vetsuisse Faculty > Institute of Veterinary Pharmacology and Toxicology
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:2009
Deposited On:10 Feb 2010 15:52
Last Modified:18 Feb 2018 00:13
Number of Pages:46
OA Status:Green
Related URLs:http://opac.nebis.ch/F/?local_base=NEBIS&con_lng=GER&func=find-b&find_code=SYS&request=005864704

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