Differential roles of CB1 and CB2 cannabinoid receptors in mast cells.
Cannabinoid modulation of immune responses is a pathological consequence of marijuana abuse and a potential outcome of therapeutic application of the drug. Moreover, endogenous cannabinoids are physiological immune regulators. In the present report, we describe alterations in gene transcription that occur after cannabinoid exposure in a mast cell line, RBL2H3. Cannabinoid exposure causes marked changes in the transcript levels for numerous genes, acting both independently of and in concert with immunoreceptor stimulation via Fc epsilon RI. In two mast cell lines, we observed mRNA and protein expression corresponding to both CB1 and CB2 cannabinoid receptor isoforms, contrary to the prevailing view that CB1 is restricted to the CNS. We show that coexpression of the two isoforms is not functionally redundant in mast cells. Analysis of signaling pathways downstream of cannabinoid application reveals that activation of extracellular signal-regulated kinase, AKT, and a selected subset of AKT targets is accomplished by CB2 ligands and nonselective CB1/CB2 agonists in mast cells. CB1 inhibition does not affect AKT or extracellular signal-regulated kinase activation by cannabinoids, indicating that CB2 is the predominant regulatory receptor for these kinases in this cell context. CB1 receptors are, however, functional in these mast cells, since they can contribute to suppression of secretory responses.
Laboratory of Cell Biology and Immunology, Queen's Center for Biomedical Research, Queen's Medical Center, Honolulu, HI 96813, USA.
Maria-Teresa
MT
Samson
Andrea
A
Small-Howard
Lori M N
LM
Shimoda
Murielle
M
Koblan-Huberson
Alexander J
AJ
Stokes
Helen
H
Turner
D000818:Animals; D002186:Cannabinoids / Q000378:metabolism* / Q000494:pharmacology; D002460:Cell Line; D003511:Cyclohexanols / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008024:Ligands; D008407:Mast Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000096:biosynthesis; D010766:Phosphorylation / Q000187:drug effects; D020033:Protein Isoforms / Q000096:biosynthesis / Q000502:physiology; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000096:biosynthesis / Q000502:physiology*; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000502:physiology; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured
D002186:Cannabinoids; C469526:Cnr2 protein, rat; D003511:Cyclohexanols; D007166:Immunosuppressive Agents; D008024:Ligands; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D011971:Receptors, Immunologic; D012702:Serotonin Antagonists; D012701:Serotonin; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases