Cannabinoid receptors and immunity
Section snippets
Ligands
Over 60 cannabinoids, each possessing a multi-ring structure, have been identified in extracts of the cannabis plant[1]. The major psychoactive cannabinoid is THC (Fig. 1), which was first purified and structurally described in 1964 (Ref. [4]) and allowed the subsequent chemical synthesis of structural analogues for use in structure–activity studies[1]. These studies provided evidence for specific binding sites linked to G proteins, especially Gi (Ref. [5]). The synthesis of analogues also led
Cannabinoid effects on immune cells
The main body of literature involving marijuana and immune modulation dates back to the 1970s. At that time, a few reports suggested that cannabis use was associated with an increased incidence of viral infections as well as allergic symptoms (reviewed in Ref. [18]). Subsequent animal studies with herpes simplex virus, Friend leukemia virus, Listeria monocytogenes, Staphylococcus albus, Treponema pallidum and Legionella pneumophila have shown that cannabinoids suppress host resistance to
Cannabinoid effects on cytokines
Cytokines play a major role in mediating the antimicrobial effects of immune cells. For example, interferons (IFNs) are powerful antiviral agents as well as immunomodulators, and interleukin 2 (IL-2) is a major growth factor for the development of immunity. If cannabinoids are immunomodulatory, they would be expected to exert some of that effect through modulation of cytokine production and function. Mouse splenocyte cultures treated with THC (10 μm range) produced less IFN, while chronic
Receptor expression and immune cells
Despite the many early studies showing that THC modulates immune function, evidence that CBRs were involved was lacking and the drug effects were believed to be mainly nonspecific interactions with lipids in cell membranes affecting the function of integral membrane proteins[2]. However, in 1992, the first report appeared showing that splenocytes expressed CB1 mRNA as measured by reverse transcriptase (RT)–PCR (Ref. [37]). A modest structure–activity relationship was shown in this study using
Concluding remarks
In summary, the evidence to date suggests that a CBR–ligand system exists in the immune system and has some role in immune homeostasis. However, the function and distribution of receptor subtypes in the various immune compartments is far from clear at this time. CB2 appears to be readily expressed but this subtype, as well as CB1, is probably upregulated in various immune cells depending upon the level of cell differentiation and/or activation. The immune system, because of its capacity to
Acknowledgements
We thank Y. Daaka, W. Zhu and L. Snella for their laboratory contributions and stimulating discussions and ideas. We also thank past and present students who have on many occasions brought new life and fresh perspective to our thinking.
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