The cannabinoid receptors agonist WIN55212-2 inhibits macrophageal differentiation and alters expression and phosphorylation of cell cycle control proteins
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The cannabinoid receptors agonist WIN55212-2 inhibits macrophageal differentiation and alters expression and phosphorylation of cell cycle control proteins

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16 pages
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In this study we investigated if and how cannabinoid receptor stimulation regulates macrophageal differentiation, which is one of the key steps in the immune effector reaction. For that reason, we used a well established differentiation model system of human U937 myelocytic leukemia cells that differentiate along the monocyte/macrophage lineage upon stimulation with the phorbol ester PMA. Constant cannabinoid receptor (CB) stimulation was performed using WIN55212-2, a potent synthetic CB agonist. We found that WIN55212-2 inhibited CB1/2-receptor-dependent PMA-induced differentiation of human myelocytic U937 cells into the macrophageal phenotype, which was associated with impaired vimentin, ICAM-1 and CD11b expression. In the presence of WIN55212-2, cdc2 protein and mRNA expression was progressively enhanced and Tyr-15-phosporylation of cdc2 was reduced in differentiating U937 cells. Additionally, p21 Waf1/Cip1 expression was up-regulated. PMA-induced apoptosis was not enhanced by WIN55212-2 and differentiation-associated c-jun expression was not altered. In conclusion, we suppose that WIN55212-2-induced signals interferes with cell-cycle-arrest-signaling in differentiating myelocytic cells and thus inhibits macrophageal differentiation. Thus, it is possible that the cannabinoid system is able to influence one of the key steps in the immune effector function, the monocytic-macrophageal differentiation by alteration of cell cycle control proteins cdc2 and p21, and is therefore representing a promising option for therapeutic intervention in exacerbated immune reactions.

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Publié par
Publié le 01 janvier 2011
Nombre de lectures 7
Langue English
Poids de l'ouvrage 1 Mo

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Paulsen et al . Cell Communication and Signaling 2011, 9 :33 http://www.biosignaling.com/content/9/1/33
R E S E A R C H Open Access The cannabinoid receptors agonist WIN55212-2 inhibits macrophageal differentiation and alters expression and phosphorylation of cell cycle control proteins Katrin Paulsen 1 , Svantje Tauber 1 , Johanna Timm 1 , Nadine Goelz 1 , Claudia Dumrese 1,2 , Alexandra Stolzing 3 , Ralf Hass 4 and Oliver Ullrich 1,5*
Abstract In this study we investigated if and how cannabinoid receptor stimulation regulates macrophageal differentiation, which is one of the key steps in the immune effector reaction. For that reason, we used a well established differentiation model system of human U937 myelocytic leukemia cells that differentiate along the monocyte/ macrophage lineage upon stimulation with the phorbol ester PMA. Constant cannabinoid receptor (CB) stimulation was performed using WIN55212-2, a potent synthetic CB agonist. We found that WIN55212-2 inhibited CB1/2-receptor-dependent PMA-induced differentiation of human myelocytic U937 cells into the macrophageal phenotype, which was associated with impaired vimentin, ICAM-1 and CD11b expression. In the presence of WIN55212-2, cdc2 protein and mRNA expression was progressively enhanced and Tyr-15-phosporylation of cdc2 was reduced in differentiating U937 cells. Additionally, p21 Waf1/Cip1 expression was up-regulated. PMA-induced apoptosis was not enhanced by WIN55212-2 and differentiation-associated c-jun expression was not altered. In conclusion, we suppose that WIN55212-2-induced signals interferes with cell-cycle-arrest-signaling in differentiating myelocytic cells and thus inhibits macrophageal differentiation. Thus, it is possible that the cannabinoid system is able to influence one of the key steps in the immune effector function, the monocytic-macrophageal differentiation by alteration of cell cycle control proteins cdc2 and p21, and is therefore representing a promising option for therapeutic intervention in exacerbated immune reactions. Keywords: Immune control, Macrophages, Differentiation, Cannabinoids
Introduction in 1990 in the brain. A few years later a second receptor Cannabinoids have been used as medicinal plant CB2 was cloned from immune cells [4,5]. The activation extracts for a long time. A lready 4000 years ago, the of CB1 and CB2 results in different cellular responses: Chinese emperor successfully treated diseases associated (i) inhibition of adenylyl c yclase and the cAMP/protein with increased immune reaction and inflammation using kinase A (PKA)-dependent pathway by inhibitory G-pro-plant extracts [1]. The fact that the signaling pathways teins (Gi) which leads to a reduced production of cAMP of the cannabinoid system are conserved throughout [6] while recent research suggests that these receptors various species suggests an evolutionary benefit [2,3]. can also stimulate cAMP prod uction by directly stimu-Cannabinoid signals can be mediated by different recep- lating G-proteins (Gs) [7] (ii) stimulation of mitogen-tors, the first cannabinoid receptor CB1 was discovered activated protein kinase (MAPK) cascade, especially the extracellular signal kinase (ERK) [8] and the p38 MAPK * Corre onde cascade [9]. Whereas the CB1 receptor is mainly, but Contrsipbutednecqeu:alollyiver.ullrich@anatom.uzh.ch not exclusively, expressed on neurons, the CB2 receptor 1 fDiZvisionh,oSfwCitezllebriloalnodgy,InstituteofAnatomy,FacultyofMedairctiicnlee,University itsorpsriimnaritlhyeprceasnenntaibniniomidmusnigencaelllssy[8s,t1e0m].iOntchleurdreectehpe-o uric Full list of author information is available at the end of the © 2011 Paulsen et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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