CB(1) and CB(2) cannabinoid receptors mediate different aspects of delta-9-tetrahydrocannabinol (THC)-induced T helper cell shift following immune activation by Legionella pneumophila infection.
Legionella pneumophila infection of mice induces proinflammatory cytokines and Th1 immunity as well as rapid increases in serum levels of IL-12 and IFNgamma and splenic IL-12Rbeta2 expression. Delta-9-tetrahydrocannabinol (THC) treatment prior to infection causes a shift from Th1 to Th2 immunity and here we demonstrate that CB(1) and CB(2) cannabinoid receptors mediate different aspects of the shift. Using cannabinoid receptor antagonists and cannabinoid receptor gene deficient mice (CB(1) (-/-) and CB(2) (-/-)), we showed that both CB(1) and CB(2) receptors were involved in the THC-induced attenuation of serum IL-12 and IFNgamma. IFNgamma production is dependent upon signaling through IL-12Rbeta2 (beta2) and THC treatment suppressed splenic beta2 message; moreover, this effect was CB(1) but not CB(2)-dependent from studies with receptor antagonists and CB1(-/-) and CB2(-/-) mice. Furthermore, observed increases in IL-4 induced by THC, were not involved in the drug effect on beta2 from studies with IL-4 deficient mice. The GATA-3 transcription factor is necessary for IL-4 production and is selectively expressed in Th2 cells. GATA-3 message levels were elevated in spleens of THC-treated and L. pneumophila-infected mice and the effect was shown to be CB(2) but not CB(1)-dependent. Furthermore, GATA-3 regulatory factors were modulated in that Notch ligand Delta4 mRNA was decreased and Jagged1 increased by THC also in a CB2-dependent manner and splenic NFkappaB p65 was increased. Together, these results indicate that CB(1) and CB(2) mediate the THC-induced shift in T helper activity in L. pneumophila-infected mice, with CB(1) involved in suppressing IL-12Rbeta2 and CB(2) involved in enhancing GATA-3.
Newton
Catherine A
CA
Department of Molecular Medicine, University of South Florida, Tampa, FL 33612, USA. cnewton@health.usf.edu
Chou
Ping-Jen
PJ
Perkins
Izabella
I
Klein
Thomas W
TW
D000818:Animals; D002135:Calcium-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D003713:Dendritic Cells / Q000187:drug effects; D013759:Dronabinol / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D050990:GATA3 Transcription Factor / Q000096:biosynthesis / Q000235:genetics; D006213:Hallucinogens / Q000494:pharmacology*; D007111:Immunity, Cellular / Q000187:drug effects*; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics; D053712:Interleukin-12 Receptor beta 2 Subunit / Q000096:biosynthesis; D000072100:Jagged-1 Protein; D007877:Legionnaires' Disease / Q000276:immunology*; D008262:Macrophage Activation / Q000187:drug effects*; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects* / Q000235:genetics; D043885:Receptor, Cannabinoid, CB2 / Q000187:drug effects* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000072099:Serrate-Jagged Proteins; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects*; D018418:Th2 Cells / Q000187:drug effects; D051996:Transcription Factor RelA / Q000096:biosynthesis / Q000235:genetics
D002135:Calcium-Binding Proteins; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D006213:Hallucinogens; D036341:Intercellular Signaling Peptides and Proteins; D053712:Interleukin-12 Receptor beta 2 Subunit; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D000072099:Serrate-Jagged Proteins; D051996:Transcription Factor RelA; D013759:Dronabinol
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