CB2 cannabinoid receptor agonist JWH-015 modulates human monocyte migration through defined intracellular signaling pathways.

Recruitment of leukocytes to inflammatory sites is crucial in the pathogenesis of chronic inflammatory diseases. The aim of this study was to investigate if activation of CB2 cannabinoid receptors would modulate the chemotactic response of human monocytes. Human monocytes treated with the CB2 agonist JWH-015 for 12-18 h showed significantly reduced migration to chemokines CCL2 and CCL3, associated with reduced mRNA and surface expression of their receptors CCR2 and CCR1. The induction of ICAM-1 in response to IFN-gamma was inhibited by JWH-015. Moreover, JWH-015 cross-desensitized human monocytes for migration in response to CCL2 and CCL3 by its own chemoattractant properties. The CB2-selective antagonist SR-144528, but not the CB1 antagonist SR-147778, reversed JWH-015-induced actions, whereas the CB2 agonist JWH-133 mimicked the effects of JWH-015. The investigation of underlying pathways revealed the involvement of phosphatidylinositol 3-kinase/Akt and ERK1/2 but not p38 MAPK. In conclusion, selective activation of CB2 receptors modulates chemotaxis of human monocytes, which might have crucial effects in chronic inflammatory disorders such as atherosclerosis or rheumatoid arthritis.

[1]  N. Stella,et al.  CB2 receptor‐mediated migration of immune cells: it can go either way , 2008, British journal of pharmacology.

[2]  Pál Pacher,et al.  Pivotal Advance: Cannabinoid‐2 receptor agonist HU‐308 protects against hepatic ischemia/reperfusion injury by attenuating oxidative stress, inflammatory response, and apoptosis , 2007 .

[3]  Elena Galkina,et al.  Vascular adhesion molecules in atherosclerosis. , 2007, Arteriosclerosis, thrombosis, and vascular biology.

[4]  K. Mackie,et al.  CB2-receptor stimulation attenuates TNF-alpha-induced human endothelial cell activation, transendothelial migration of monocytes, and monocyte-endothelial adhesion. , 2007, American journal of physiology. Heart and circulatory physiology.

[5]  L. Liaudet,et al.  Pharmacological inhibition of CB1 cannabinoid receptor protects against doxorubicin-induced cardiotoxicity. , 2007, Journal of the American College of Cardiology.

[6]  C. Lunn,et al.  Sch35966 is a potent, selective agonist at the peripheral cannabinoid receptor (CB2) in rodents and primates , 2007, British journal of pharmacology.

[7]  B. Cravatt,et al.  Decreased age-related cardiac dysfunction, myocardial nitrative stress, inflammatory gene expression, and apoptosis in mice lacking fatty acid amide hydrolase. , 2007, American journal of physiology. Heart and circulatory physiology.

[8]  S. Werner,et al.  Attenuation of Allergic Contact Dermatitis Through the Endocannabinoid System , 2007, Science.

[9]  H. Pan,et al.  Cannabinoid‐2 receptor mediates protection against hepatic ischemia/reperfusion injury , 2007, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[10]  A. Koch,et al.  Macrophages and their products in rheumatoid arthritis , 2007, Current opinion in rheumatology.

[11]  M. Nagarkatti,et al.  CB2 cannabinoid receptor agonist, JWH-015, triggers apoptosis in immune cells: potential role for CB2-selective ligands as immunosuppressive agents. , 2007, Clinical immunology.

[12]  S. Ward,et al.  Temporal variation in CB2R levels following T lymphocyte activation: evidence that cannabinoids modulate CXCL12-induced chemotaxis. , 2007, International immunopharmacology.

[13]  C. Trautwein,et al.  CB1 cannabinoid receptor antagonism: A new strategy for the treatment of liver fibrosis , 2007, Hepatology.

[14]  F. Mach,et al.  Leukocyte recruitment in atherosclerosis: Potential targets for therapeutic approaches? , 2006, Cellular and Molecular Life Sciences CMLS.

[15]  P. Pacher,et al.  The Endocannabinoid System as an Emerging Target of Pharmacotherapy , 2006, Pharmacological Reviews.

[16]  K. Mackie,et al.  Involvement of Neuronal Cannabinoid Receptor CB1 in Regulation of Bone Mass and Bone Remodeling , 2006, Molecular Pharmacology.

[17]  R. Ganju,et al.  Cannabinoid receptor CB2 modulates the CXCL12/CXCR4-mediated chemotaxis of T lymphocytes. , 2006, Molecular immunology.

[18]  Peter Libby,et al.  The immune response in atherosclerosis: a double-edged sword , 2006, Nature Reviews Immunology.

[19]  R. Ransohoff,et al.  The many roles of chemokines and chemokine receptors in inflammation. , 2006, The New England journal of medicine.

[20]  Jay S. Fine,et al.  A Novel Cannabinoid Peripheral Cannabinoid Receptor-Selective Inverse Agonist Blocks Leukocyte Recruitment in Vivo , 2006, Journal of Pharmacology and Experimental Therapeutics.

[21]  B. Frenkel,et al.  Peripheral cannabinoid receptor, CB2, regulates bone mass. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[22]  S. Gordon,et al.  Monocyte and macrophage heterogeneity , 2005, Nature Reviews Immunology.

[23]  U. Kornak,et al.  Cannabinoid receptor type 2 gene is associated with human osteoporosis. , 2005, Human molecular genetics.

[24]  T. Arefieva,et al.  MCP-1-stimulated chemotaxis of monocytic and endothelial cells is dependent on activation of different signaling cascades. , 2005, Cytokine.

[25]  Beatriz León,et al.  Monocyte-derived dendritic cells. , 2005, Seminars in immunology.

[26]  T. Klein.  Cannabinoid-based drugs as anti-inflammatory therapeutics , 2005, Nature Reviews Immunology.

[27]  F. Mach,et al.  Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice , 2005, Nature.

[28]  M. Remberger,et al.  Increased gene expression of chemokine receptors is correlated with acute graft-versus-host disease after allogeneic stem cell transplantation. , 2005, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[29]  Liying Li,et al.  Antifibrogenic role of the cannabinoid receptor CB2 in the liver. , 2005, Gastroenterology.

[30]  P. Sacerdote,et al.  The nonpsychoactive component of marijuana cannabidiol modulates chemotaxis and IL-10 and IL-12 production of murine macrophages both in vivo and in vitro , 2005, Journal of Neuroimmunology.

[31]  A. Zernecke,et al.  Chemokines: Key Regulators of Mononuclear Cell Recruitment in Atherosclerotic Vascular Disease , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[32]  P. Soubrié,et al.  SR147778 [5-(4-Bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-N-(1-piperidinyl)-1H-pyrazole-3-carboxamide], a New Potent and Selective Antagonist of the CB1 Cannabinoid Receptor: Biochemical and Pharmacological Characterization , 2004, Journal of Pharmacology and Experimental Therapeutics.

[33]  R. Tuma,et al.  Win 55212-2, a cannabinoid receptor agonist, attenuates leukocyte/endothelial interactions in an experimental autoimmune encephalomyelitis model , 2004, Multiple sclerosis.

[34]  C. Newton,et al.  The cannabinoid system and immune modulation , 2003, Journal of leukocyte biology.

[35]  P. Mcgeer,et al.  Reduction of human monocytic cell neurotoxicity and cytokine secretion by ligands of the cannabinoid‐type CB2 receptor , 2003, British journal of pharmacology.

[36]  I. Lossos,et al.  Optimization of quantitative real-time RT-PCR parameters for the study of lymphoid malignancies , 2003, Leukemia.

[37]  V. Sánchez-Margalet,et al.  Human leptin promotes survival of human circulating blood monocytes prone to apoptosis by activation of p42/44 MAPK pathway. , 2002, Cellular immunology.

[38]  Michael T. Fisher,et al.  Targeting CB2 cannabinoid receptors as a novel therapy to treat malignant lymphoblastic disease. , 2002, Blood.

[39]  S. Ali,et al.  Leucocyte chemotaxis: Examination of mitogen‐activated protein kinase and phosphoinositide 3‐kinase activation by Monocyte Chemoattractant Proteins‐1, ‐2, ‐3 and ‐4 , 2002, Clinical and experimental immunology.

[40]  A. Sanyal,et al.  Endocannabinoids acting at vascular CB1 receptors mediate the vasodilated state in advanced liver cirrhosis , 2001, Nature Medicine.

[41]  M. Yamakuchi,et al.  Simultaneous measurement of anandamide and 2-arachidonoylglycerol by polymyxin B-selective adsorption and subsequent high-performance liquid chromatography analysis: increase in endogenous cannabinoids in the sera of patients with endotoxic shock. , 2001, Analytical biochemistry.

[42]  H. Arai,et al.  Distinct Signaling Pathways for MCP-1-dependent Integrin Activation and Chemotaxis* , 2001, The Journal of Biological Chemistry.

[43]  H. Byrnes,et al.  Evaluation of Signal Transduction Pathways in Chemoattractant-Induced Human Monocyte Chemotaxis , 2001, Inflammation.

[44]  W. Owen,et al.  beta(2)-Microglobulin modified with advanced glycation end products delays monocyte apoptosis. , 2001, Kidney international.

[45]  R. Horuk,et al.  Specialized roles of the chemokine receptors CCR1 and CCR5 in the recruitment of monocytes and T(H)1-like/CD45RO(+) T cells. , 2001, Blood.

[46]  B. Cambien,et al.  Signal transduction involved in MCP-1-mediated monocytic transendothelial migration. , 2001, Blood.

[47]  P. Sacerdote,et al.  In vivo and in vitro treatment with the synthetic cannabinoid CP55,940 decreases the in vitro migration of macrophages in the rat: involvement of both CB1 and CB2 receptors , 2000, Journal of Neuroimmunology.

[48]  S. Yu,et al.  3-(1',1'-Dimethylbutyl)-1-deoxy-delta8-THC and related compounds: synthesis of selective ligands for the CB2 receptor. , 1999, Bioorganic & medicinal chemistry.

[49]  R. Pertwee,et al.  Pharmacology of cannabinoid receptor ligands. , 1999, Current medicinal chemistry.

[50]  R. Snyderman,et al.  Chemoattractant Receptor Cross-desensitization* , 1999, The Journal of Biological Chemistry.

[51]  P. Casellas,et al.  Gi protein modulation induced by a selective inverse agonist for the peripheral cannabinoid receptor CB2: implication for intracellular signalization cross-regulation. , 1999, Molecular pharmacology.

[52]  P. Casellas,et al.  SR 144528, the first potent and selective antagonist of the CB2 cannabinoid receptor. , 1998, The Journal of pharmacology and experimental therapeutics.

[53]  E. Ellis,et al.  Activation of peripheral CB1 cannabinoid receptors in haemorrhagic shock , 1997, Nature.

[54]  G. Feldman,et al.  Regulation of leukocyte adhesion and signaling in inflammation and disease , 1996, Journal of leukocyte biology.

[55]  S. Galiègue,et al.  Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. , 1995, European journal of biochemistry.

[56]  L. Lindbom,et al.  Leukocyte‐Cell Adhesion: A Molecular Process Fundamental in Leukocyte Physiology , 1990, Immunological reviews.