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INFLAMMATION AND IMMUNOPHARMACOLOGY

Methylenedioxymethamphetamine Suppresses Production of the Proinflammatory Cytokine Tumor Necrosis Factor- Independent of a -Adrenoceptor-Mediated Increase in Interleukin-10

Department of Physiology, Trinity College Institute of Neuroscience, Trinity College, Dublin, Ireland (T.J.C.).; and Department of Pharmacology, National University of Ireland, Galway, Ireland (T.J.C., A.H., J.P.K.)

Recent data suggest that 3,4-methylenedioxymethamphetamine (MDMA; "Ecstasy") has marked immunosuppressive properties. In this study, we investigate the effect of MDMA on production of the anti-inflammatory cytokine interleukin (IL)-10 in response to an in vivo challenge with bacterial lipopolysaccharide (LPS). Our data demonstrate that both acute and repeated administration of MDMA increases production of LPS-induced IL-10 in vivo, and this increase correlates inversely with the ability of MDMA to suppress the proinflammatory cytokine tumor necrosis factor (TNF)-. Despite this correlation, immunoneutralization of IL-10 does not reverse the suppressive effect of MDMA on LPS-induced TNF- production, indicating that suppression of this proinflammatory cytokine is not mediated by IL-10. In vitro exposure to MDMA does not mimic the immunosuppressive cytokine phenotype induced in vivo, suggesting that these immunosuppressive effects are not mediated by a direct action on monocytes per se. As MDMA activates that hypothalamic pituitary adrenal axis and sympathetic nervous system, we examined the role of glucocorticoids and catecholamines in its immunosuppressive actions. However, the immunosuppressive cytokine phenotype induced by MDMA was not altered by adrenalectomy, sympathetic denervation, or ganglionic blockade, indicating that neither glucocorticoids nor adrenal/sympathetic-derived catecholamines mediate these immunosuppressive effects of MDMA. Interestingly, -adrenoceptor blockade completely inhibited the increase in IL-10 induced by MDMA without altering the suppression of TNF-. Taken together, these data demonstrate a role for -adrenoceptor activation in the ability of MDMA to increase LPS-induced IL-10 and highlight a mechanistic dissociation between the ability of MDMA to increase IL-10 and suppress production of the proinflammatory cytokine TNF-.

Address correspondence to: Dr. Thomas Connor, Department of Physiology, Trinity College, Dublin 2, Ireland. E-mail: connort{at}tcd.ie