Endocannabinoids and the Immune System

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Endocannabinoids are believed to control immune functions and play a role in immune homeostasis. Immune cells express both CB1 and CB2 receptors, secrete endocannabinoids and have functional cannabinoid transport and breakdown mechanisms [15,16]. Human peripheral blood immune cells are reported to have different degrees of cannabinoid receptor expression with the following rank order: B cells > NK cells > monocytes > polymorphonuclear neutrophils > CD8 lymphocytes > CD4 lymphocytes [17]. The CB1 receptors are densely expressed in the central nervous system and mediate neurobehavioral effects. The expression levels of CB2 receptors in immune cells are 10–100 times greater than CB1 receptors. Moreover, CB2 receptor mRNA was also detected in the cortex of lymph nodes and the nodular corona of Peyer’s patches [18].

Endocannabinoid biosynthesis and signaling in the immune system
There is significant biochemical evidence to suggest that biosynthesis, uptake and degradation of endocannabinoids occur in macrophages and leukocytes [15,16,19]. This finding supports the role of endocannabinoids as local modulators of immune and inflammatory reactions. It was observed that both RBL-2H3 basophil cells and J774 macrophages can biosynthesize AEA and PEA through hydrolysis of corresponding N-acylphosphatidylethanolamines. Both these cell lines could inactivate the two bioactive acylethanolamide by sequestering radiolabelled AEA and PEA from the culture medium. Furthermore, following uptake by basophils, AEA and PEA competed for the same inactivating enzyme which catalyzed their hydrolysis to ethanolamine. Maccarrone et al. demonstrated that LPS down-regulated FAAH expression and increased AEA levels in human peripheral lymphocytes [20,21]. The effect of this endotoxin on FAAH was not mediated by AEA-induced activation of cannabinoid receptors. In fact, the stimulatory action of LPS on AEA levels was considered to be due to the inhibition of FAAH as suggested by the observation that an increase in levels of AEA was also induced by an irreversible FAAH inhibitor. Varga et al. demonstrated that rat platelets and macrophages contained the endogenous cannabinoid, 2-AG, and in vitro exposure to LPS markedly increased 2-AG levels [22]. Thus, these results indicated that immune cells take part in regulating peripheral endocannabinoid system and endocannabinoid homeostasis. It has been shown that human mast cells also take up AEA followed by its hydrolysis by FAAH [21]. Thus, mast cells contribute towards regulation of peripheral endocannabinoid system thereby affecting endocannabinoid mediated effect in inflammation, vascular tone and other immune interactions [21].

The CB1 and CB2 receptors negatively regulate adenylyl cyclase activity through pertussis toxin-sensitive GTP-binding protein. Endocannabinoids have been well known to exhibit this property, which is considered to be an important mechanism of lymphocyte regulation [4,23]. As cAMP signaling cascade has a positive regulatory role in immune cell function, cannabinoid receptor stimulation could antagonize the early events in immune cell activation. Besides, CB1 and CB2 receptors also stimulate mitogen activated protein kinase (MAPK) activity. Endocannabinoids have also been shown to induce MAPK pathway, which is a CB2 receptor-mediated response [24]. Thus, it is now evident that cannabinoid receptor stimulation in the immune system by the endocannabinoids triggers a complex regulation and modulation of cAMP pathways and the cannabinoid receptor stimulation of MAP kinase plays a key role in immune homeostasis and control. The importance of CB2 receptor activation in the immunomodulatory effects of endocannabinoids has been recognized and is supported by anti-inflammatory effects of CB2 receptor activation in many pathological conditions and disparate diseases ranging from inflammatory pain, myocardial infarction, stroke, hepatic I/R injury, gastrointestinal inflammatory disorders [25,26], liver inflammatory disorders [27] and atherosclerosis [28].

The effect of cannabinoids on immune functions appears to be transient which would allow the inhibitory effects to be overcome when the immune system needs to be activated during infections. This is supported by the downregulation of cannabinoid receptor expression when the immune cells are activated. Thus, the transient nature of cannabinoids on the immune system suggests that the side effects of the potential therapy may be minimal. Although the function of cannabinoid receptor on immune cells and the cross-talk between the immune system and endocannabinoids is yet to be fully defined, based on available data, we can hypothesize that the endocannabinoid signaling in lymphoid tissue may provide a tonic control of immune cell activation and therefore limit spontaneous activation of immune cell function. There have been a number of recent studies which have demonstrated that the endocannabinoids have both inhibitory effects and stimulatory impact on the immune system and may be actually important in homeostasis or control of the immune reactions.

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