Effects of targeted deletion of cannabinoid receptors CB1 and CB2 on immune competence and sensitivity to immune modulation by Delta9-tetrahydrocannabinol.
The role of cannabinoid receptors, CB1 and CB2, in immune competence and modulation by Delta9-tetrahydrocannabinol (Delta9-THC) was investigated in CB1(-/-)/CB2(-/-) mice. Immunofluorescence analysis of splenic leukocytes showed no significant differences in the percentage of T cell subsets, B cells, or macrophages between wild-type and CB1(-/-)/CB2(-/-) mice. Lymphoproliferative control responses to PHA, phorbol ester plus ionomycin, or LPS and sensitivity to suppression by Delta9-THC showed no profound differences between the two genotypes, although some differences were observed in control baseline responses. Likewise, similar control responses and sensitivity to Delta9-THC were observed in mixed lymphocyte responses (MLR) and in IL-2 and IFN-gamma production in both genotypes. Conversely, humoral immune responses showed a markedly different profile of activity. Delta9-THC suppressed the in vivo T cell-dependent, anti-sheep RBC (anti-sRBC) IgM antibody-forming cell (AFC) response in wild-type but not in CB1(-/-)/CB2(-/-) mice, and the in vitro anti-sRBC IgM response in CB1(-/-)/CB2(-/-) splenocytes was too low to rigorously assess CB1/CB2 involvement in modulation by Delta9-THC. Conversely, comparable in vitro IgM AFC control responses to LPS and CD40 ligand (CD40L) activation were observed in the two genotypes. Interestingly, LPS-induced IgM responses were refractory to suppression by Delta9-THC, regardless of genotype, and CD40L-induced IgM responses were only suppressed by Delta9-THC in wild-type but not in CB1(-/-)/CB2(-/-) B cells. Collectively, we demonstrate differential involvement of CB1 and/or CB2 in immune modulation by Delta9-THC and in some control responses. Moreover, CB1/CB2 involvement was observed in humoral responses requiring CD40-initiated signaling for suppression by Delta9-THC.
Springs
Alison E B
AE
Centre for Integrative Toxicology, Cell and Molecular Biology Program, Michigan State University, East Lansing, MI 48824-1317, USA.
Karmaus
Peer W F
PW
Crawford
Robert B
RB
Kaplan
Barbara L F
BL
Kaminski
Norbert E
NE
D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation; D013759:Dronabinol / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D007075:Immunoglobulin M; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism*; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology
D018712:Analgesics, Non-Narcotic; D007075:Immunoglobulin M; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D013759:Dronabinol
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