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Inhibition of macrophage inducible protein expression by delta-9-tetrahydrocannabinol
G A Cabral1, K Fischer-Stenger
1Department of Microbiology and Immunology, Medical College of Virginia/Virginia Commonwealth University, Richmond 23298-0678.
Abstract:
Macrophages have been shown to undergo a sequential process to full activation in response to priming and triggering signals such as gamma interferon (IFN gamma) 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 gamma. THC also suppressed protein expression in response to LPS. P388D1 and RAW264.7 macrophage-like cells, treated with Con A supernatant or IFN gamma, 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 gamma, 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 P388D1 macrophage class II Ia molecules of the major histocompatibility complex (MHC), in response to Con A supernatant and IFN gamma, was inhibited. THC also altered the expression of tumor necrosis factor alpha (TNF alpha) 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.
Insights
Delta-9-tetrahydrocannabinol (THC) suppresses macrophage activation by altering protein expression. This suggests THC impacts immune cell function by inhibiting key effector molecules, reverting cells to an unactivated state.
Area of Science:
- Immunology
- Cell Biology
- Pharmacology
Background:
- Macrophages play a crucial role in the immune response, with their activation state indicated by protein expression profiles.
- Priming and triggering signals like gamma interferon (IFN-γ) and lipopolysaccharide (LPS) induce sequential macrophage activation.
- Delta-9-tetrahydrocannabinol (THC), a major marijuana component, is known to affect cellular processes.
Purpose of the Study:
- To investigate the effect of THC on macrophage activation and protein expression.
- To determine if THC alters the protein profiles associated with different stages of macrophage activation.
- To explore THC's impact on the expression of specific effector molecules during macrophage activation.
Main Methods:
- Utilized iso-Dalt two-dimensional gel electrophoresis to analyze protein profiles of macrophage-like cell lines (P388D1 and RAW264.7).
- Treated macrophages with priming agents (Concanavalin A supernatant, IFN-γ) and activating agents (LPS) with and without THC.
- Measured changes in the expression of specific molecules, including MHC class II Ia and tumor necrosis factor alpha (TNF-α).
Main Results:
- THC treatment, in conjunction with priming or activating signals, reverted macrophage protein profiles to resemble those of unprimed cells.
- THC inhibited the induction of specific proteins associated with macrophage priming and activation.
- THC suppressed the expression of P388D1 macrophage MHC class II Ia molecules and RAW264.7 TNF-α.
Conclusions:
- THC significantly alters macrophage functional activities by suppressing the expression of effector molecules.
- The observed changes in protein profiles suggest THC interferes with the macrophage activation cascade.
- THC's impact on effector molecule expression indicates a potential mechanism for its immunomodulatory effects.