INHIBITION OF PROTEIN-KINASE-A AND CYCLIC-AMP RESPONSE ELEMENT (CRE)-SPECIFIC TRANSCRIPTION FACTOR-BINDING BY DELTA(9)-TETRAHYDROCANNABINOL(DELTA(9)-THC) - A PUTATIVE MECHANISM OF CANNABINOID-INDUCED IMMUNE MODULATION

Delta 9-Tetrahydrocannabinol (Delta 9-THC) binding to cannabinoid rece ptors induces an inhibition in adenylate cyclase activity through the engagement of a pertussis toxin-sensitive GTP-binding protein. In this study we investigated the ramifications of decreased cyclic AMP (cAMP ) formation by Delta(9)-THC on signaling events through the cAMP pathw ay distal to adenylate cyclase in mouse splenocytes. Delta(9)-THC trea tment produced a marked and concentration related decrease in forskoli n-inducible protein kinase A (PKA) activity. This decrease in kinase a ctivity was due to an inhibition in cAMP formation and not through a d irect effect on the kinase as evidenced by the fact that PKA activity could not be modulated directly by Delta(9)-THC in the presence of exo genous cAMP. One of the primary roles of PKA in this signaling pathway is to activate transcription factors for subsequent binding to cAMP r esponse elements (CRE) present in the promoter region of cAMP-responsi ve genes. In the present studies, we observed that forskolin treatment of splenocytes resulted in a rapid activation of trans-acting factor binding to the CRE, which peaked at 30-60 min and whose binding was re pressed concentration dependently in the presence of Delta(9)-THC. As with forskolin, mitogenic stimulation including anti-CD3 mAb or phorbo l ester plus ionomycin treatment of splenocytes induced CRE binding ac tivity, which was maximal around 60 min and was suppressed by Delta 9- THC treatment. In conclusion, these data indicate that cAMP mediated s ignal transduction is inhibited by Delta(9)-THC and consequently leads to a decrease in the activation of transcription factors that bind to CRE regulatory sites. (C) 1997 Elsevier Science Inc.