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Vol. 302, Issue 2, 451-465, August 2002

Delta 9-Tetrahydrocannabinol-Induced Apoptosis in the Thymus and Spleen as a Mechanism of Immunosuppression in Vitro and in Vivo

Robert J. McKallip, Catherine Lombard, Billy R. Martin, Mitzi Nagarkatti and Prakash S. Nagarkatti

Departments of Microbiology and Immunology (R.J.M., C.L., M.N.) and Pharmacology and Toxicology (B.R.M., P.S.N.), Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia

Delta 9-Tetrahydrocannabinol (THC), the main psychoactive component of marijuana has been shown to suppress the immune response. However, the exact mechanism of THC-induced immunosuppression remains unclear. In the current study, we tested the hypothesis that exposure to THC leads to the induction of apoptosis in lymphocyte populations. Splenocytes of C57BL/6 mice cultured in the presence of 10 µM or greater concentrations of THC showed significantly reduced proliferative response to mitogens, including anti-CD3 monoclonal antibodies (mAbs), concanavalin A (Con A), and lipopolysaccharide (LPS) in vitro. Thymocytes and naive and activated splenocytes exposed to 10 µM or 20 µM THC showed significantly increased levels of apoptosis. Treatment with CB2 antagonist inhibited THC-induced apoptosis in thymocytes and activated splenocytes. Administration of 10 mg/kg body weight of THC into C57BL/6 mice led to thymic and splenic atrophy as early as 6 h after treatment. This effect could be partially inhibited by treatment with a caspase inhibitor in vivo. THC exposure led to reductions in the numbers of all subpopulations of splenocytes and thymocytes examined. Functional studies revealed that splenocytes from THC-treated mice had significantly reduced proliferative response to anti-CD3 mAbs, Con A, and LPS in vitro. Finally, thymocytes and splenocytes exposed to THC in vivo exhibited apoptosis upon in vitro culture. Together, these results suggest that in vivo exposure to THC can lead to significant suppression of the immune response by induction of apoptosis.

0022-3565/02/3022-0451$07.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


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