| Title | Cannabinoid receptor type 1 and 2-mediated increase in cyclic AMP inhibits T cell receptor-triggered signaling. | | Author(s) | Borner C, Smida M, Hollt V, Schraven B, Kraus J | | Institution | University of Magdeburg, Germany. | | Source | J Biol Chem 2009 Oct 26. | | Abstract | The aim of this study was to characterize inhibitory mechanisms on T cell receptor signaling mediated by the cannabinoid receptors CB1 and CB2. Both receptors are coupled to Gi/o proteins, which are associated with inhibition of cyclic AMP formation. In human primary and Jurkat T lymphocytes, activation of CB1 by R(+)-methanandamide, CB2 by JWH015, and both by delta-9-tetrahydrocannabinol induced a short decrease in cyclic AMP lasting less than one hour. However, this decrease was followed by a massive (up to 10-fold) and sustained (at least up to 48 hours) increase in cyclic AMP. Mediated by the cyclic AMP-activated protein kinase A (PKA) and C-terminal Src kinase (Csk) the cannabinoids induced a stable phosphorylation of the inhibitory Tyr-505 of the leukocyte-specific protein tyrosine kinase (Lck). By thus arresting Lck in its inhibited form, the cannabinoids prevented the dephosphorylation of Lck at Tyr-505 in response to T cell receptor activation, which is necessary for the subsequent initiation of T cell receptor signaling. In this way the cannabinoids inhibited the T cell receptor-triggered signaling, i. e. the activation of the zeta-chain-associated protein kinase of 70 kDa (Zap 70), the linker for activation of T cells (LAT), the mitogen-activated protein kinase (MAPK), the induction of interleukin-2 and T cell proliferation. All effects of the cannabinoids were blocked by the CB1- and CB2-antagonists AM281 and AM630. These findings help to better understand immunosuppressive effects of cannabinoids, and explain beneficial effects of these drugs in the treatment of T cell-mediated autoimmune disorders like multiple sclerosis. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19858202 |
|
