Cannabinoids Δ9-Tetrahydrocannabinol and Cannabidiol Differentially Inhibit the Lipopolysaccharide-activated NF-κB and Interferon-β/STAT Proinflammatory Pathways in BV-2 Microglial Cells

Abstract

Cannabinoids have been shown to exert anti-inflammatory activities in various in vivo and in vitro experimental models as well as ameliorate various inflammatory degenerative diseases. However, the mechanisms of these effects are not completely understood. Using the BV-2 mouse microglial cell line and lipopolysaccharide (LPS) to induce an inflammatory response, we studied the signaling pathways engaged in the anti-inflammatory effects of cannabinoids as well as their influence on the expression of several genes known to be involved in inflammation. We found that the two major cannabinoids present in marijuana, ⌬ 9 -Tetrahydrocannabinol (THC) 3 is a major constituent of Cannabis and serves as an agonist of the cannabinoid receptors CB1 (located mainly in neural cells) and CB2 (located mainly on immune cells). The second major constituent of Cannabis extract is cannabidiol (CBD), which is virtually inactive at the CB1 and CB2 receptors (1). Thus, because of its negligible activity at the CB1 receptor, CBD lacks the psychoactive effects that accompany the use of THC. Moreover, CBD was demonstrated to antagonize some undesirable effects of THC, including intoxication, sedation, and tachycardia, while sharing neuroprotective, anti-oxidative, anti-emetic, and anti-carcinogenic properties (2-4). Both THC and CBD have been shown to exert anti-inflammatory properties and to modulate the function of immune cells, including suppression of humoral response, immune cell proliferation, maturation, and migration, and antigen presentation (5-9). Despite increasing amounts of such observations, the molecular mechanisms involved in these cannabinoid-mediated effects are not yet fully understood.Microglial cells are resident macrophages of the central nervous system and serve as early host defense against pathogens. Activation of microglial cells leads to the release of proinflammatory and neurotoxic factors and serves as part of the neuroinflammatory process (10). The BV-2 murine microglial cell line is known to retain morphological, phenotypic, and functional properties associated with freshly isolated microglia such as expression of nonspecific esterase activity, phagocytic ability, and the absence of peroxidase activity (11,12). Furthermore, these cells release lysozyme and, when stimulated, interleukin (IL)-1 and tumor necrosis factor ␣ (11, 12). Close similarities between BV-2 and primary microglia in mechanisms mediating microglial stimulations, e.g. by lipopolysaccharide (LPS), S100B, or ␤-amyloid, were reported (13). These properties make BV-2 cells an appropriate model for studying the activation of microglia in vitro. It has recently been shown that BV-2 cells express elements of the cannabinoid signaling systems, including the presence of endocannabinoids, i.e. anandamide and 2-arachidonoylglycerol, and cannabinoid or cannabinoid- 3 The abbreviations used are: THC, ⌬ 9 -tetrahydrocannabinol; CBD, cannabidiol; abn-CBD, abnormal cannabidiol; STAT, signal transducers and activators of transcription; IL, interleukin; IFN, ...

Cannabidiol exerts sebostatic and antiinflammatory effects on human sebocytes

“…TRIB3 is known to inhibit the NF-κB pathway (50), and, furthermore, CBD has already been reported to exert its antiinflammatory actions via inhibition of the NF-κB signaling (51). Importantly, we found that CBD cotreatment indeed prevented the LPS-induced phosphorylation (hence inactivation) of the inhibitory IκBα and phosphorylation (hence activation) of the p65 (RelA) NF-κB isoform ( Figure 8B).…”

“…Thorough assessment of the microarray data highlighted the putative role of TRIB3, a known inhibitor of proinflammatory NF-κB signaling (50). In addition, inhibition of NF-κB signaling plays a crucial role in the development of CBDmediated antiinflammatory actions in other systems (51). RNA imediated selective gene silencing of TRIB3 in human sebocytes (Supplemental Figure 15, A and B) fully abrogated the ability of CBD to inhibit LPS-induced proinflammatory responses (Figure 8A).…”

The Endocannabinoid/Endovanilloid N-Arachidonoyl Dopamine (NADA) and Synthetic Cannabinoid WIN55,212-2 Abate the Inflammatory Activation of Human Endothelial Cells

“…Although it is clear that several plant-derived (i.e. phytocannabinoids) and synthetic cannabinoids possess immunomodulatory activity, prior studies have primarily focused on their effects on leukocytes and microglia without assessing their effects on the endothelium, which is known to be centrally involved in acute inflammatory disorders such as sepsis (17)(18)(19). In sepsis, the persistent, direct, and unresolved engagement of endothelial Toll-like receptors (TLRs) by microbial components, and the sustained secretion of endogenous inflammatory mediators, such as tumor necrosis factor (TNF)␣ and interleukin (IL)-1␤, lead to endothelial activation and dysfunction (20 -24).…”

The potential use of cannabidiol in the therapy of metabolic syndrome

“…Végső soron a CBD 5 mg/kg/nap dózisban lymphopeniát már kiválthat, de csak a B-, T-, Tc-és Th-sejtek számának csökkenése jelentkezik, azaz a specifi kus immunválasz gyengül, míg a megfi gyelések szerint a nem specifi kus, tumorra és vírusokra adott válasz erősö-dik [35].…”