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EDITORIAL FOCUS
1Section on Oxidative Stress and Tissue Injury, Laboratory of Physiological Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland; and 2Department of Physiology, New York Medical College, Valhalla, New York
ENDOCANNABINOIDS are endogenous lipid mediators, generated by practically all cell types in both the central nervous system and peripheral tissues, that exert a wide range of biological effects (e.g., psychoactive, analgesic, cardiovascular, and anti-inflammatory, etc.) similar to those of cannabis via the activation of two main G protein-coupled cannabinoid receptors: CB1 and CB2 receptors (7, 9, 13, 17, 20). Emerging recent evidence also supports the possible existence of additional, yet-unidentified CB receptors, and endocannabinoids may also exert multiple effects unrelated to CB receptors (5). The dysregulation of the endocannabinoid system has recently been implicated in many human diseases, and its pharmacological modulation holds tremendous promise in the treatment of pain, neurodegenerative, metabolic, cardiovascular, and inflammatory disorders as well as cancer (7, 9, 17, 20).
The CB2 receptor was previously considered to be expressed predominantly in immune and hematopoietic cells (for a review, see Ref. 17), but more recent studies have also found it in the brain (26), myocardium (11, 16), and endothelial cells of various origins (for a review, see Ref. 18). Since CB2 receptor activation mediates various beneficial effects in preclinical disease models, the development of selective CB2 receptor agonists for therapeutic indications, which are devoid of psychoactive properties of CB1 agonists, has attracted considerable interest over the past couple of years (9, 17, 20). Indeed, numerous recent studies have demonstrated anti-inflammatory effects of CB2 receptor activation in a multitude of disparate diseases and pathological conditions, ranging from neurodegenerative disorders (2, 19), inflammatory pain (8), atherosclerosis (24, 25), myocardial injury (6, 11), cerebral injury (28), and hepatic ischemia-reperfusion injury (3, 18, 23) to gastrointestinal inflammatory disorders (27) and liver inflammation and fibrosis (12), to mention just a few.
The migration of inflammatory cells, mainly monocytes, into the arterial wall is a crucial event during atherogenesis. This process is orchestrated by chemokines and chemokine receptors as well as adhesion molecules. Steffens and colleagues (25), using apolipoprotein E knockout mice, have previously provided experimental evidence on a possible role of CB2 receptors in atherosclerosis progression. Oral administration of low doses of 
9-tetrahydrocannabinol (THC), which exerts various effects on both CB1 and CB2 receptors, inhibited atherosclerotic plaque progression in mice. They also demonstrated CB2 receptor-expressing immune cells in mouse and human atherosclerotic plaques. Furthermore, lymphoid cells isolated from THC-treated mice had reduced proliferation capacity and decreased IFN-
production, and THC inhibited macrophage chemotaxis in vitro. Since all the above-mentioned effects could largely be attenuated by a selective CB2 but not CB1 receptor antagonist, the authors hypothesized the crucial involvement of CB2 receptors on immune cells in atherosclerosis progression (25).
Several previous, mostly in vitro, studies have investigated the role of CB1/CB2 receptor activation on baseline or stimulated inflammatory and other cell migration, with both increases and decreases of cell migration being reported, depending on the trigger/condition, endocannabinoid, synthetic agonist/antagonist, and cell type used (for reviews, see Refs. 9, 10, and 14). Therefore, it is important to better understand the complex role of endocannabinoid signaling in inflammatory cell chemotaxis/migration and the potential consequences of its pharmacological modulation by selective agonists and/or antagonists.
In their current study, Montecucco and colleagues (15) investigated the effect of CB2 cannabinoid receptor activation on the chemotactic response of human monocytes. They found that the CB2 receptor agonists JWH-015 and/or JWH-133 modulated the recruitment of human monocytes by various immediate and delayed effects. Prolonged (12–18 h) preincubation with JWH-015 reduced monocyte migration to chemokines CCL2 and CCL3. This effect was likely due to reduced expression of the cognate chemokine receptors CCR2 and CCR1 and reduced IFN--induced ICAM-1 expression. These interesting findings should provide a basis for further research into the role of CB2 receptors in cardiovascular inflammatory diseases using genetically modified mice. Montecucco et al. convincingly showed that short-term incubation with JWH-015 itself was a chemoattractant for monocytes. Migration experiments using increasing JWH-015 gradients suggested that the cannabinoid-induced migration was directed chemotaxis rather than random movement. Moreover, JWH-015 cross-desensitized human monocytes for migration to CCL2 and CCL3. Indeed, it has been reported that certain chemoattractants desensitize the cells toward a further stimulation with other chemoattractants (1). This may have physiological relevance, as systemic administration of JWH-015 may desensitize the cells toward migration to inflammatory sites. The authors also showed that the above-mentioned effects of JWH-015 could be mimicked by another CB2-selective agonist, JWH-133, and largely attenuated by a CB2-selective antagonist, SR-144528, supporting the involvement of CB2 receptors. Finally, the authors provided evidence that both short- and long-term effects were dependent on phosphatidylinositol 3-kinase/Akt and ERK1/2 signaling. Further studies are evidently needed to elucidate the role of the aforementioned pathways in animal models of inflammatory diseases.
In conclusion, these new findings, coupled with recent evidence demonstrating that CB2 receptor activation also attenuates TNF-
-induced endothelial cell activation, transendothelial migration of monocytes, and monocyte/neutrophil-endothelial adhesion (3, 4, 21, 23) as wells as decreases TNF--induced proliferation and migration of human coronary vascular smooth muscle cells by modulating distinct signaling pathways (22), provide important new mechanistic insights on the possible pleiotropic effects of CB2 receptor activation in atherosclerosis and other inflammatory disorders.
GRANTS
This work was supported by National Institutes of Health Grants HL-077256 and HL-43023 (to Z. Ungvári) and the National Institutes of Health Intramural Research Program (to P. Pacher).
FOOTNOTES
Address for reprint requests and other correspondence: Z. Ungvári, Dept. of Physiology, New York Medical College, Valhalla, NY 10595 (e-mail: zoltan_ungvari{at}nymc.edu); P. Pacher, Sect. of Oxidative Stress and Tissue Injury, NIH/NIAAA, 5625 Fishers Ln., MSC-9413, Bethesda, MD 20892-9413 (e-mail: pacher{at}mail.nih.gov)
REFERENCES
-induced human endothelial cell activation, transendothelial migration of monocytes, and monocyte-endothelial adhesion. Am J Physiol Heart Circ Physiol 293: H2210–H2218, 2007.
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