In rats, repeated administration of CBD (IP) at a dose of 5 mg/kg caused a significant decrease in total leukocyte number and a significant fall in total numbers of T, B, and both T helper and T cytotoxic lymphocyte subsets. This immunosuppressive effect did not affect the total numbers of NK and NKT cells that are responsible for the primary, nonspecific antiviral and antitumor immune response. In contrast, administration of CBD at a dose of 2.5 mg/kg increased the total and percentage NKT cells numbers, and the percentage number of NK cells. The results suggest that repeated treatment with CBD inhibits specific immunity by reduction of T, B, T cytotoxic, and T helper cell numbers, and may enhance nonspecific antiviral and antitumor immune response related to NK and NKT cells (Ignatowska-Jankowska et al., 2009).
Cultured mouse healthy thymocytes and EL-4 thymoma cells are equally sensitive to CBD-induced apoptosis. Cancerous Leukemia and glioma cells, on the other hand, are relatively sensitive to CBD-induced apoptosis compared to their normal counterparts: monocytes and glial cells. Combined, this suggests that CBD may be therapeutic in the treatment of some types of malignancies but not necessarily all (Lee et al., 2008).
Human macrophages express GPR55 receptors. Activation of GPR55 in these cells increases lipid accumulation, blocks cholesterol efflux and is pro-inflammatory and pro-atherogenic. Blocking GPR55 with CBD counteracts these effects suggesting therapeutic potential (Lanuti et al., 2015).
In keratinocytes, activation of CB1 receptors by Anandamide suppresses the release of IL-12 and IL-23 and subsequent polarization of pro-inflammatory TH1 and TH17 cells. This suggests Anandamide normally functions to suppress inflammation and CB1 activation might have therapeutic potential (Chiurchiù et al., 2016).
In a rat model of systemic inflammation (IV LPS injection) CB2 receptor activation reduced microvascular leukocyte adherence and increased blood flow (Toguri et al., 2015).
In a mouse model of proliferative vitreoretinopathy stimulation of CB2 (HU-308) reduced microglial activation, leukocyte-endothelial adhesion and pro-inflammatory cykokine production while CB2 inhibition (AM-630) increased inflammation (Szczesniak et al., 2016).
Osteoblasts and osteoclasts express CB2 receptors. In rats CB2 agonist HU-308 protects from LPS-induced periodontitis and subsequent bone loss suggesting CB2 receptors could be a therapeutic target (Ossola et al., 2016).
In a mouse model of arthritis, Anandamide, OEA and PEA are anti-inflammatory. Anandamide, OEA and PEA downregulate pro-inflammatory IL-6, IL-8 and MMP-3 in synovial fibroblasts via activation of TRPV1 and TRPA1 (Lowin et al., 2015).
In a mouse model of osteoarthritis activation of CB2 was anti-inflammatory while inflammation was more severe in CB2 deficient mice (Sophocleous et al., 2015).
In children with juvenile idiopathic arthritis the Q36R variant of CB2 was associated with increased relapse rates (Bellini et al., 2015).
In a mouse model of lung inflammation, CBD (20/80 mg/kg IP) decreased leukocyte migration and production of pro-inflammatory cytokines and improved lung function (Ribeiro et al., 2014).
In human blood eosinophils from allergic donors CB2 expression was higher than in eosinophils from non-allergic donors. Stimulation of CB2 (JHW-133) potently enhanced chemoattractant-induced eosinophil shape change, chemotaxis, CD11b surface expression and adhesion as well as production of reactive oxygen species. In mice, CB2 stimulation aggravated allergen-induced pulmonary inflammation suggesting CB2 inhibition might be beneficial in allergic inflammation treatment (Frei et al., 2016).
In a mouse model of asthma, mice lacking CB2 receptors exhibited elevated numbers of pulmonary natural killer (NK) cells and reduced numbers of group 2 innate lymphoid cells (ILC2s), cells yet were resistant to the induction of allergic inflammation. This suggests that NK cells serve to limit ILC2 activation and subsequent allergic airway inflammation. CB2 inhibition may present an important target to modulate NK cell response during pulmonary inflammation (Ferrini et al., 2016).
Administering CBD into naive mice triggers robust induction of CD11b(+)Gr-1(+) myeloid-derived suppressor cells (MDSC) in the peritoneum, which expressed functional arginase 1, and potently suppressed T cell proliferation ex vivo. Furthermore, CBD-MDSC suppressed LPS-induced acute inflammatory response upon adoptive transfer in vivo. The induction of suppressor cells by CBD is dependent on PPARγ (Hegde et al., 2015).
In LPS-stimulated cultured RAW264.7 macrophages 5-HT-DHA conjugate (100-500 nM) was anti-inflammatory by suppression of IL-17 and IL-23 signalling (Poland et al., 2016).
The proliferation of RAW267.4 cells was suppressed by culture with β-caryophyllene (50, 100 and 200 µg/ml of medium), suggesting an anti-inflammatory effect (Yamaguchi and Levy, 2016).
Proinflammatory cytokines IL-1β, IL-6 and TNF-α can up-regulate CB1 and CB2 on human whole blood and peripheral blood mononuclear cells (Jean-Gilles et al., 2015), potentially priming these cells for immunosuppression.
Hempseed oil is a rich and balanced source of omega-6 and omega-3 polyunsaturated fatty acids (PUFAs). Dietary hempseen oil increases skin inoleic acid (18:2n6) and alpha-linolenic acid (18:3n3), and gamma-linolenic acid (GLA; 18:3n6) levels and improves skin dryness and itchiness (p=0.027) and decreases dermal medication usage (p=0.024) (Callaway et al., 2005) in patients with dermatitis.
In astrocytes, Anandamide can be pro-inflammatory via CB1 activation resulting in increased microglial activation after brain insult (Vázquez et al., 2015).
In stimulated human peripheral blood cells, Anandamide was shown to diminish interleukin-6 and interleukin-8 production at low nanomolar concentrations (3-30 nM) but inhibited the production of TNF-alpha, interferon-gamma, interleukin-4 and p75 TNF-alpha soluble receptors at higher concentrations (0.3-3 microM). Palmitoylethanolamide inhibited interleukin-4, interleukin-6, interleukin-8 synthesis and the production of p75 TNF-alpha soluble receptors at concentrations similar to those of Anandamide but failed to influence TNF-alpha and interferon-gamma production. The effect of both compounds on interleukin-6 and interleukin-8 production disappeared with an increase in the concentration used. Neither Anandamide nor palmitoylethanolamide influenced interleukin-10 synthesis. delta9-Tetrahydrocannabinol exerted a biphasic action on pro-inflammatory cytokine production. TNF-alpha, interleukin-6 and interleukin-8 synthesis was maximally inhibited by 3 nM delta9-tetrahydrocannabinol but stimulated by 3 microM delta9-tetrahydrocannabinol, as was interleukin-8 and interferon-gamma synthesis. The level of interleukin-4, interleukin-10 and p75 TNF-alpha soluble receptors was diminished by 3 microM delta9-tetrahydrocannabinol. These results suggest that the inhibitory properties of Anandamide, palmitoylethanolamide and delta9-tetrahydrocannabinol are determined by the activation of the peripheral-type Cannabinoid receptors, and that various endogenous fatty acid ethanolamides may participate in the regulation of the immune response (Berdyshev et al., 1997).
Genetic deletion or pharmacological inhibition of DAGL-β (lowering brain 2AG by ±83% and Anandamide by ±42%) protects against lipopolysaccharide (LPS)-induced inflammatory responses in mouse peritoneal macrophages, and reverses LPS-induced allodynia in mice (Wilkerson et al., 2017).
Genetic or pharmacological ablation of MAGL leads to significantly reduced fever responses in both centrally or peripherally-administered lipopolysaccharide or interleukin-1β-induced fever models in mice (Sanchez-Alavez et al., 2015).
Administration of PEA to the anterior cingulate cortex attenuates inflammatory pain behavior in a CB1-dependent way, possibly by increasing Anandamide levels in the brain (Okine et al., 2016).
In experimental autoimmune encephalomyelitis, overexpression of CB1R significantly inhibited the expression of NF-kB/p65 and TLR-4 as well as levels of IL-1β, IL-6, and TNF-α, followed by a decrease of IL-17 and an increase of IL-10 in the spinal cord of mice. The percentage of M1 marker CD11b(+)CD16/32(+) cells was decreased, while the percentage of M2 marker CD11b(+)CD206(+) and CD11b(+)IL-10(+) cells was elevated in splenic mononuclear cells (MNCs) of mice with overexpression of CB1R. Interestingly, overexpression of CB1R dramatically enhanced the expression of neurotrophic NT-3, BDNF, and GDNF in the spinal cord. These results indicate that local overexpression of CB1R in the spinal cord exhibited neuroprotective effects in EAE, mainly suppressing inflammatory microenvironment and elevating neurotrophic factors, slightly declining IL-1β and IL-17 in the spleen, and increased IL-10 in the brain (Lou et al., 2015).
In Caco-2 cells treated with IFNγ and TNFα, OEA (via TRPV1) and PEA (via PPARα) prevented or reversed the cytokine-induced increased permeability suggesting a potential therapeutic role for OEA and PEA in intestinal inflammation. Preventing the degradation of OEA and PEA, by inhibition of FAAH, enhanced their effect (Karwad et al., 2016). Anandamide and 2AG play similar anti-inflammatory roles in a CB1-dependent way (Karwad et al., 2017).
In mice, excisional skin wound healing is promoted by CB2 activation and subsequent reduced inflammation and scar formation and accelerated re-epitheliazation (Wang et al., 2016).
Mice deficient for FAAH have higher endocannabinoid levels and are more susceptible to preterm birth upon LPS challenge due to enhanced decidual senescence suggesting a pro-inflammatory role of endocannabinoids here (Sun et al.). This effect was attenuated by metformin/inhibition of mTOR.
CB1 agonism promotes food intake and adipocyte growth and as such can contribute to the metabolic syndrome. CB2 agonism (HU-308) prevents metabolic syndrome-evoked polarization of adipose tissue macrophages toward the M1-like pro-inflammatory type and reduced nociceptive hypersensitivity, but had no effect on weight gain (Schmitz et al., 2015).
Mast cell activation is an inflammatory process in diseases such as atopic dermatitis, psoriasis, and contact dermatitis. Topical application of CB1 agonists dose-dependently suppresses mast cell proliferation, skin recruitment and histamine release suggesting a role for CB1 activation in the treatment of antigen-related inflammation (Nam et al., 2016).
In rats ototoxic events induce cochlear CB2 expression suggesting therapeutic potential for cannabinoids in ear inflammation (Martín-Saldaña et al., 2016).
Intra-peritoneal administration of CB receptor ligands, including CB1 receptor antagonists and CB2 receptor agonists, ameliorate dialysis-related peritoneal fibrosis (Yang et al., 2017).
In a guinea pig model of lung inflammation (TNF-α and LPS) THC was antitussive, bronchodilatory and anti-inflammatory in a CB1 and CB2 dependent way. THCV was somewhat antitussive. CBD, CBDA, CBC and CBG were neither antitussive, nor bronchodilatory or anti-inflammatory (Makwana et al., 2015).
In another study on Calu-3 bronchial epithelial cells, the anti-inflammatory effect of THC was CB2, but not CB1-dependent (Shang et al., 2016).
In mice, experimental ear inflammation (DNFB) and dermatitis (mite antigen) a CB2 agonist (S-777469) prevented swelling and eosinophil accumulation, presumably by blocking 2AG-mediated inflammation (Haruna et al., 2017).
In the mouse collagen model of arthritis, CBD dose-dependently inhibited inflammation. The dose dependency showed a bell-shaped curve, with an optimal effect at 5 mg/kg per day i.p. or 25 mg/kg per day orally (Malfait et al., 2000).
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