Cannabinoid-induced apoptosis: Regulation of normal and transformed immune cells.

摘要

Cannabis has been used for recreational and medicinal purposes since ancient times. The major limitation in the clinical use of cannabis stems from the psychotropic effects that it mediates. However, the recent discovery of the endogenous cannabinoid system and distinct cannabinoid receptors on cells of the immune and nervous system has opened exciting new possibilities on the clinical applications of cannabinoids. Recent studies from our laboratory and elsewhere suggested that cannabinoids mediate anti-inflammatory and anti-cancer properties. However, the precise mechanisms through which the cannabinoids exert these properties are not clear. In the current study, we demonstrate that delta 9-tetrahydrocannabinol (THC) induces apoptosis in Jurkat (T cell leukemia) cells via signaling through the intrinsic mitochondrial pathway, with a potential amplification through the extrinsic death receptor pathway involving Bid cleavage. We also demonstrate that a synthetic CB2 receptor selective agonist (JWH-015) induces immunosuppression in vivo by triggering apoptosis in T cells, and could potentially be used as a non-psychotropic therapeutic agent in the treatment of inflammatory diseases. Interestingly, we found that mature immune cells but not the progenitor Lin- c-kit+ cells from the bone marrow are susceptible to cannabinoid-induced apoptosis. Also, a bone marrow transplant can successfully reconstitute the thymus of a lethally irradiated host despite THC treatment, suggesting that cannabinoid-induced immunosuppression is transient and that patients should be able to recover from the immunosuppressive effects upon cessation of the treatment. The unique property of THC to kill mature immune cells but not the progenitor cells, provides an excellent opportunity to use cannabinoids to treat a wide range of clinical disorders, particularly graft-versus-host disease. While apoptosis induction in tumor cells is critical for an effective anti-cancer therapy, we also demonstrate that certain tumors express FasL and tumor-derived FasL is indeed immunosuppressive in vivo. This is an important factor that may decide the effectiveness of cancer chemo- and immunotherapy. Together, these studies shed new light on complex interactions between cannabinoids and their receptors expressed on normal and transformed immune cells and how such interactions can be exploited to develop new therapeutic modalities.