Effect of the Psychoactive Metabolite of Marijuana, Δ9-Tetrahydrocannabinol (THC), on the Synthesis of Tumor Necrosis Factor by Human Large Granular Lymphocytes

doi:10.1006/cimm.1994.1060

Cellular Immunology

Volume 154, Issue 1, March 1994, Pages 99-108

https://doi.org/10.1006/cimm.1994.1060 Get rights and content

Abstract

The natural killer cell (NK)/³polymorphonuclear neutrophil axis has recently been identified to be important in early defense against the opportunistic fungi, Candida albicans. Repression of this system is therefore likely to contribute to susceptibility to opportunistic infections. Δ⁹-Tetrahydrocannabinol (THC), an active constituent of marijuana, has been reported to be immunosuppressive at concentrations that exceed attainable plasma levels. In this report, we examine the possibility that human large granular lymphocytes (LGL) can be immunosuppressed by exposure to THC at physiologically relevant concentrations and probed two functions associated with LGL i.e., cytokine production and tumoricidal activity. We find that these low levels of THC inhibit tumor necrosis factor-α (TNF) induction from LGL by C. albicans and are dependent upon THC dose (0.005-5.0 μg/ml) and length of exposure (0.05 3.0 hr). Northern blot analysis indicates that the downregulation of TNF production from LGL by THC resides at the mRNA level. Moreover, exposure of LGL to physiological THC concentrations (0.01 2.0 μg/ml) diminishes their cytolytic activity against K562 tumor cells.

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Cited by (40)

In vivo and in vitro anti-inflammatory activity evaluation of Lebanese Cannabis sativa L. ssp. indica (Lam.)
2021, Journal of Ethnopharmacology
Citation Excerpt :
CBD has also completely suppressed the production of TNF-α in LPS-stimulated RAW264.7 macrophages (Ben-Shabat et al., 2006). Moreover, both CBD and THC caused a decrease in the levels of IL-1β and TNF-α in mitogen-activated human peripheral blood mononuclear cells (Kusher et al., 1994; Watzl et al., 1991). Cannabis sativa leaf extracts with varying proportions of terpenoids and cannabinoids, specifically CBD and THC was found to reduce the expression levels of i-NOS, COX-2 and interleukin-1 β (IL-1β) in synovial fibroblast cell line SW982 (Duangnin et al., 2017).
Cannabis sativa L. is an aromatic annual herb belonging to the family Cannabaceae and it is widely distributed worldwide. Cultivation, selling, and consumption of cannabis and cannabis related products, regardless of its use, was prohibited in Lebanon until April 22, 2020. Nevertheless, cannabis oil has been traditionally used unlawfully for many years in Lebanon to treat diseases such as arthritis, diabetes, cancer and few neurological disorders.
The present study aims to evaluate the phytochemical and anti-inflammatory properties of a cannabis oil preparation that is analogous to the illegally used cannabis oil in Lebanon.
Dried Cannabis flowers were extracted with ethanol without any purification procedures to simulate the extracts sold by underground dealers in Lebanon. GC/MS was performed to identify chemical components of the cannabis oil extract (COE). In vivo anti-inflammatory effect of COE was evaluated by using carageenan- and formalin-induced paw edema rat models. TNF-α production were determined by using LPS-activated rat monocytes. Anti-inflammatory markers were quantified using Western blot.
Chemical analysis of COE revealed that cannabidiol (CBD; 59.1%) and tetrahydrocannabinol (THC; 20.2%) were found to be the most abundant cannabinoids.Various monoterpenes (α-Pinene, Camphene, β-Myrecene and D-Limonene) and sesquiterpenes (β-Caryophyllene, α-Bergamotene, α-Humelene, Humulene epoxide II, and Caryophyllene oxide) were identified in the extract. Results showed that COE markedly suppressed the release of TNF-α in LPS-stimulated rat monocytes. Western blot analysis revealed that COE significantly inhibited LPS-induced COX-2 and i-NOS protein expressions and blocked the phosphorylation of MAPKs, specifically that of extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK) and p38 MAPK. COE displayed a significant inhibition of paw edema in both rat models. Histopathological examination revealed that COE reduced inflammation and edema in chronic paw edema model.
The current findings demonstrate that COE possesses remarkable in vivo and in vitro anti-inflammatory activities which support the traditional use of the Lebanese cannabis oil extract in the treatment of various inflammatory diseases including arthritis.
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THC is the main psychoactive compound found in marijuana. A number of studies over the past few decades, both in vitro and in vivo, have demonstrated that THC down-regulates the inflammatory process through various mechanisms. Similar findings have been demonstrated with CBD, the other major bioactive component of marijuana. Given the essential role that inflammation plays in early wound healing, it is possible that marijuana, or its individual constituents, may impact this process. Herein, we review the existing literature related to the effects of THC on inflammation and potentially wound healing, and discuss how this connection may be relevant from a surgical perspective.
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Nanomolar concentrations of Δ9-tetrahydrocannabinol or cannabidiol are demonstrated to enhance mitogen-induced degradation of tryptophan in human peripheral blood mononuclear cells in dependence of CB1- or CB2-receptor activation. In contrast, suppression of this pathway by cannabinoids in the micromolar concentration range was achieved independent of cannabinoid receptor activation. Both cannabinoids also suppressed tryptophan degradation in myelomonocytic THP-1 cells stimulated with lipopolysaccharide. We conclude, that suppression of tryptophan degradation by cannabinoids via indoleamine-2,3-dioxygenase, which is independent of cannabinoid receptor activation, might enhance the availability of tryptophan for serotonin biosynthesis and consequently can be important in the action of cannabinoids to improve mood disturbances.
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Since the discovery of the cannabinoid receptors and their endogenous ligands, significant advances have been made in studying the physiological function of the endocannabinoid system. The presence of cannabinoid receptors on cells of the immune system and anecdotal and historical evidence suggesting that cannabis use has potent immuno-modulatory effects, has led to research directed at understanding the function and role of these receptors within the context of immunological cellular function. Studies from chronic cannabis smokers have provided much of the evidence for immunomodulatory effects of cannabis in humans, and animal and in vitro studies of immune cells such as T cells and macrophages have also provided important evidence. Cannabinoids can modulate both the function and secretion of cytokines from immune cells. Therefore, cannabinoids may be considered for treatment of inflammatory disease. This review article will highlight recent research on cannabinoids and how they interact with the immune system and also their potential use as therapeutic agents for a number of inflammatory disorders.
Autocrine and paracrine regulation of lymphocyte CB2 receptor expression by TGF-β
2002, Biochemical and Biophysical Research Communications
The marijuana-derived cannabinoid Δ⁹-tetrahydrocannabinol (THC) has been shown to be immunosuppressive. We report that THC induces the immunosuppressive cytokine TGF-β by human peripheral blood lymphocytes (PBL). The ability of THC to stimulate TGF-β production was blocked by the CB2 receptor specific antagonist SR144528 but not by the CB1 specific antagonist AM251. Furthermore, our data suggest that TGF-β actively regulates lymphocyte CB2 receptor expression in an autocrine and paracrine manner. Whereas the addition of recombinant TGF-β to PBL cultures downregulated CB2 receptor expression, anti-TGF-β antibody treatment increased CB2 receptor expression. We conclude that one mechanism by which THC contributes to immune suppression is by stimulating an enhanced production of lymphocyte TGF-β.
Marijuana: A tumour growth promoter?
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Regular ArticleEffect of the Psychoactive Metabolite of Marijuana, Δ9-Tetrahydrocannabinol (THC), on the Synthesis of Tumor Necrosis Factor by Human Large Granular Lymphocytes

Abstract

Regular Article
Effect of the Psychoactive Metabolite of Marijuana, Δ⁹-Tetrahydrocannabinol (THC), on the Synthesis of Tumor Necrosis Factor by Human Large Granular Lymphocytes