Cannabinoid receptor CB2 modulates the CXCL12/CXCR4-mediated chemotaxis of T lymphocytes.
Cannabinoids have been shown to influence the immune system. However, their immunomodulatory effects have not been extensively studied. In this investigation, we have observed that both primary and Jurkat T cells express a functional cannabinoid receptor 2 (CB(2)). Furthermore, both the synthetic cannabinoids CP55,940 and WIN55,212-2, as well as the CB(2)-selective agonist JWH-015, caused a significant inhibition of the chemokine CXCL12-induced and CXCR4-mediated chemotaxis of Jurkat T cells, as well as their transendothelial migration. Involvement of the CB(2) receptor was further confirmed by partial reversal of the inhibition using the CB(2)-specific antagonist, AM630. Similarly, CP55,940 and JWH-015 inhibited the CXCL12-induced chemotaxis of primary CD4(+) and CD8(+) T lymphocytes. Further investigation of signaling studies to delineate the mechanism of inhibition revealed that cannabinoids enhance CXCL12-induced p44/42 MAP kinase activity. However, enhanced MAP kinase activity was not responsible for the inhibition of chemotaxis. This suggests that cannabinoids differentially regulate CXCR4-mediated migration and MAP kinase activation in T cells. Cannabinoids were also found to downregulate the PMA-enhanced enzyme activity of matrix metalloproteinase-9, which is known to play an important role in transendothelial migration. This study provides novel information regarding cannabinoid modulation of functional effects in T cells.
Ghosh
Sharmistha
S
Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
Preet
Anju
A
Groopman
Jerome E
JE
Ganju
Ramesh K
RK
D002118:Calcium / Q000378:metabolism; D002186:Cannabinoids / Q000276:immunology / Q000494:pharmacology*; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000276:immunology / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D003510:Cyclohexanes / Q000494:pharmacology; D003511:Cyclohexanols; D004730:Endothelium, Vascular / Q000502:physiology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D019169:Jurkat Cells; D061965:Matrix Metalloproteinase Inhibitors; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010636:Phenols / Q000494:pharmacology; D043885:Receptor, Cannabinoid, CB2 / Q000235:genetics / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D014471:Umbilical Veins / Q000166:cytology
C515255:CXCL12 protein, human; D002186:Cannabinoids; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D003510:Cyclohexanes; D003511:Cyclohexanols; D007166:Immunosuppressive Agents; D007211:Indoles; D061965:Matrix Metalloproteinase Inhibitors; D010636:Phenols; D043885:Receptor, Cannabinoid, CB2; D019718:Receptors, CXCR4; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; D020928:Mitogen-Activated Protein Kinases; D002118:Calcium; C094023:iodopravadoline; C402944:JHW 015