title: Antagonism of cannabinoid receptor 2 pathway suppresses IL-6-induced immunoglobulin IgM secretion.
abstract: BACKGROUND
  Cannabinoid receptor 2 (CB2) is expressed predominantly in the immune system, particularly in plasma cells, raising the possibility that targeting the CB2 pathway could yield an immunomodulatory effect. Although the role of CB2 in mediating immunoglobulin class switching has been reported, the effects of targeting the CB2 pathway on immunoglobulin secretion per se remain unclear.
  
  
  METHODS
  Human B cell line SKW 6.4, which is capable of differentiating into IgM-secreting cells once treated with human IL-6, was employed as the cell model. SKW 6.4 cells were incubated for 4 days with CB2 ligands plus IL-6 (100 U/ml). The amount of secreted IgM was determined by an ELISA. Cell proliferation was determined by the 3H-Thymidine incorporation assay. Signal molecules involved in the modulation of IgM secretion were examined by real-time RT-PCR and Western blot analyses or by using their specific inhibitors.
  
  
  RESULTS
  We demonstrated that CB2 inverse agonists SR144528 and AM630, but not CB2 agonist HU308 or CB1 antagonist SR141716, effectively inhibited IL-6-induced secretion of soluble IgM without affecting cell proliferation as measured by thymidine uptake. SR144528 alone had no effects on the basal levels of IgM in the resting cells. These effects were receptor mediated, as pretreatment with CB2 agonist abrogated SR144528-mediated inhibition of IL-6 stimulated IgM secretion. Transcription factors relevant to B cell differentiation, Bcl-6 and PAX5, as well as the protein kinase STAT3 pathway were involved in the inhibition of IL-6-induced IgM by SR144528.
  
  
  CONCLUSIONS
  These results uncover a novel function of CB2 antagonists and suggest that CB2 ligands may be potential modulators of immunoglobulin secretion.
authors.forename: Rentian
authors.initials: R
authors.lastname: Feng
authors.forename: Christine A
authors.initials: CA
authors.lastname: Milcarek
authors.affiliation: Department of Pharmaceutical Sciences, Computational Chemical Genomics Screening Center, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA. xix15@pitt.edu.
authors.forename: Xiang-Qun
authors.initials: XQ
authors.lastname: Xie
mesh_terms: D001892:Camphanes / Q000494:pharmacology; D002186:Cannabinoids / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D007075:Immunoglobulin M / Q000378:metabolism*; D007211:Indoles / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology*; D051757:PAX5 Transcription Factor / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D051560:Proto-Oncogene Proteins c-bcl-6; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077285:Rimonabant; D050796:STAT3 Transcription Factor / Q000378:metabolism
chemical_list: C084103:BCL6 protein, human; D001892:Camphanes; D002186:Cannabinoids; D004268:DNA-Binding Proteins; C508600:IL6 protein, human; D007075:Immunoglobulin M; D007211:Indoles; D015850:Interleukin-6; D051757:PAX5 Transcription Factor; C497281:PAX5 protein, human; D010880:Piperidines; D051560:Proto-Oncogene Proteins c-bcl-6; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C110630:SR 144528; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C402416:HU 308; D000077285:Rimonabant; C094023:iodopravadoline