THC has been shown both in humans and experimental animals to have immunomodulatory properties. For example, marijuana smokers may show impaired immunological functions, including deficiency of blood leukocyte blastogenesis to mitogens. Detailed studies with mice have shown that animals given THC can show marked immunomodulation, including suppression of antibody formation, deficient cytokine production. However, recent studies have also shown that lymphoid cells evince enhanced production or release or IL1, but suppression of IL2 and interferon production.
Synthetic cannabinoid, dimethylheptyl-11 oic acid (DMH-11C), is a derivative of THC-11 acid and has been shown to be orally active in ameliorating symptoms in acute and chronic inflammation models. Drug treatment suppresses the leukocyte influx in response to IL-1ß and TNF- injection. The drug effect on chronic inflammation was also tested using the adjuvant arthritis model in rats. Again, DMH-11C treatment attenuated the joint swelling that developed over time in the animals. Little was presented as to the mechanisms of the drug effects other than to show evidence suggesting that DMH-11C inhibited cyclooxygenase 2, an enzyme known to be involved the pathophysiology of inflammation.
Smoking Marijuana and Cytokines
Has been reported the effect of human marijuana smoking on cytokine production. In this study, pulmonary alveolar macrophages were removed from four subject groups and studied in tissue. The four groups were nonsmokers, or smokers of either cigarettes, marijuana, or cocaine. Macrophages were isolated and tested for various immune activities including the production of TNF- , GM-CSF, IL-6, and TGFß in response to LPS. Interestingly, the authors found that marijuana smoking alone resulted in a decrease in the macrophage production of TNF- , IL-6, and GM-CSF. Cells from smokers of cigarettes or cocaine were fully competent to produce these cytokines. On the other hand, TGFß production was not affected by marijuana or tobacco smoking but was decreased in cells from cocaine smokers. Although mechanisms of these drug effects were not presented, it was speculated that the suppression by marijuana smoking of inflammatory cytokines and the coincident neutral effect on anti-inflammatory cytokines such as TGFß might lead to an imbalance in host defenses conducive to the spread of pulmonary infections and tumors.
THC injection into mice suppressed the production of the Th1 cytokine, IFN , lowering resistance to infection.
Endocannabinoids and Cytokines
At the beginning of this century many studies focused on endoannabinoids. It was disovered that anandamide treatment also increases cytokine-induced proliferation in mouse bone marrow cells. Furthermore, specific myeloid cell line, proliferated to a greater extent in the presence of anandamide, and the growth factor effect was observed when anandamide was co-cultured with factors other than IL-3, such as GM-CSF, G-CSF, and erythropoietin. Paradoxically, the anandamide effect was not shared by other cannabimimetic agents, but the effect was dependent upon the expression of CB2. The authors concluded that anandamide is a synergistic growth stimulator for hematopoietic cells; however, the molecular link between CB2 signaling and growth factor receptor signaling was unclear. In this regard, the CB2 gene has been described as a proto-oncogene and appears to be the target of murine leukemia virus insertion and subsequent tumor formation
Mechanism of cannabinoid action
Anandamide was shown to stimulate MAP kinase activity and like proliferation this effect was not block by the SR compounds. From these results, and because MAP kinase was also stimulated by arachidonic acid, the authors concluded that anandamide was activating biological processes in a nonreceptor-mediated way. This is not surprising for fatty acid compounds that can readily penetrate the cell membrane, and in fact this has been suggested in other studies. Whatever the mechanisms, endogenous cannabimimetics may participate in the growth factor-induced maturation and differentiation of hematopoietic cells, thus playing a role in the growth and development of immune function.
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Francesco Licciardi e Matteo Manfredi
