Inhibition of macrophage inducible protein expression by delta-9-tetrahydrocannabinol

Macrophages have been shown to undergo a sequential process to full activation in response to priming and triggering signals such as gamma interferon (IFN γ) and bacterial lipopolysaccharide (LPS). These cells also may be driven directly to full activation by exposure to relatively high concentrations of LPS. Each of the stages to activation is associated with differential protein expression suggesting that newly synthesized proteins are associated with the functional activities attributable to that activation state. These observations indicate that protein profiles may serve as a barometer of the macrophage activation state. Delta-9-tetrahydrocannabinol (THC), the major psychoactive component in marijuana, was shown to inhibit inducible protein expression in response to the priming agents Concanavalin A (Con A) supernatant and IFN γ. THC also suppressed protein expression in response to LPS. P388D 1 and RAW264.7 macrophage-like cells, treated with Con A supernatant of IFN γ, exhibited restructuring of protein profiles based on iso-Dalt two-dimensional gel electrophoresis. Protein profile restructuring, distinctive from that elicited in response to priming agents, was seen for macrophages treated with LPS. Treatment of macrophages with Con A supernatant, IFN γ, or LPS in concert with THC (10 −7 M to 10 −5 M), resulted in the generation of protein profiles whose patterns reverted approximately to those of unprimed or unactivated macrophages. THC was shown to alter the expression of select proteins whose induction is associated with macrophage priming or activation. The expression of P388D 1 macrophage class II la molecules of the major histocompatibility complex (MHC), in response to Con A supernatant and IFN γ, was inhibited. THC also altered the expression of tumor necrosis factor α (TNF α) elicited by RAW264.7 cells in response to LPS. These results suggest that THC alters macrophage functional activities, at least in part, by suppressing their capacity to express effector molecules elicited in response to priming and activating signals.