Genomic and functional changes induced by the activation of the peripheral cannabinoid receptor CB2 in the promyelocytic cells HL-60. Possible involvement of the CB2 receptor in cell differentiation.
The function of the peripheral cannabinoid receptor (CB2), which is mainly expressed on hematopoietic cells, remains an enigma. In an attempt to decipher its role, we used Affymetrix DNA chips to investigate the gene expression profile of the promyelocytic cells HL-60 transfected with the CB2 receptor and activated with the cannabinoid agonist CP 55,940. Agonist exposure of these cells led to an activation of a mitogen-activated protein kinase cascade and a receptor desensitization, indicating a functional coupling of the transfected receptors. At the genomic level, activation of the CB2 receptors induced an up-regulation of nine genes involved in cytokine synthesis, regulation of transcription, and cell differentiation. A majority of them are under the control of the transcription factor NF-kappaB, whose nuclear translocation was demonstrated. Many features of the transcriptional events, reported here for the first time, appeared to be related to an activation of a cell differentiation program, suggesting that CB2 receptors could play a role in the initialization of cell maturation. Moreover, we showed that CB2-activated wild-type HL-60 cells developed properties usually found in host defense effector cells such as an enhanced release of chemotactic cytokines and an increased motility, characteristic of more mature cells of the granulocytic-monocytic lineage.
Derocq
J M
JM
Sanofi-Synthélabo, 34184 Montpellier Cedex 04, France.
Jbilo
O
O
Bouaboula
M
M
Ségui
M
M
Clère
C
C
Casellas
P
P
D001892:Camphanes / Q000494:pharmacology; D002186:Cannabinoids / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002465:Cell Movement / Q000187:drug effects; D003511:Cyclohexanols / Q000494:pharmacology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000819:agonists / Q000378:metabolism*; D014162:Transfection
D001892:Camphanes; D002186:Cannabinoids; D003511:Cyclohexanols; D016207:Cytokines; D016328:NF-kappa B; D011720:Pyrazoles; D012333:RNA, Messenger; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; C110630:SR 144528; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; D020928:Mitogen-Activated Protein Kinases