title: Human lung-resident macrophages express CB1 and CB2 receptors whose activation inhibits the release of angiogenic and lymphangiogenic factors.
abstract: Macrophages are pivotal effector cells in immune responses and tissue remodeling by producing a wide spectrum of mediators, including angiogenic and lymphangiogenic factors. Activation of cannabinoid receptor types 1 and 2 has been suggested as a new strategy to modulate angiogenesis in vitro and in vivo. We investigated whether human lung-resident macrophages express a complete endocannabinoid system by assessing their production of endocannabinoids and expression of cannabinoid receptors. Unstimulated human lung macrophage produce 2-arachidonoylglycerol,N-arachidonoyl-ethanolamine,N-palmitoyl-ethanolamine, and N-oleoyl-ethanolamine. On LPS stimulation, human lung macrophages selectively synthesize 2-arachidonoylglycerol in a calcium-dependent manner. Human lung macrophages express cannabinoid receptor types 1 and 2, and their activation induces ERK1/2 phosphorylation and reactive oxygen species generation. Cannabinoid receptor activation by the specific synthetic agonists ACEA and JWH-133 (but not the endogenous agonist 2-arachidonoylglycerol) markedly inhibits LPS-induced production of vascular endothelial growth factor-A, vascular endothelial growth factor-C, and angiopoietins and modestly affects IL-6 secretion. No significant modulation of TNF-α or IL-8/CXCL8 release was observed. The production of vascular endothelial growth factor-A by human monocyte-derived macrophages is not modulated by activation of cannabinoid receptor types 1 and 2. Given the prominent role of macrophage-assisted vascular remodeling in many tumors, we identified the expression of cannabinoid receptors in lung cancer-associated macrophages. Our results demonstrate that cannabinoid receptor activation selectively inhibits the release of angiogenic and lymphangiogenic factors from human lung macrophage but not from monocyte-derived macrophages. Activation of cannabinoid receptors on tissue-resident macrophages might be a novel strategy to modulate macrophage-assisted vascular remodeling in cancer and chronic inflammation.
authors.affiliation: Departments of *Translational Medical Sciences and Center for Basic and Clinical Immunology Research and Neuroscience, Reproductive and Odontostomatological Sciences, University of Naples Federico II, Naples, Italy; Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Naples, Italy; Endocannabinoid Research Group, Institute of Protein Biochemistry, Consiglio Nazionale delle Ricerche, Naples, Italy; Thoracic Surgery Unit, Second University of Naples, Naples, Italy; Division of Allergy and Clinical Immunology, University of Salerno, Salerno, Italy; and Consiglio Nazionale delle Ricerche Institute of Experimental Endocrinology and Oncology "G. Salvatore," Naples, Italy.
authors.forename: Rosaria I
authors.initials: RI
authors.lastname: Staiano
authors.affiliation: Departments of *Translational Medical Sciences and Center for Basic and Clinical Immunology Research and Neuroscience, Reproductive and Odontostomatological Sciences, University of Naples Federico II, Naples, Italy; Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Naples, Italy; Endocannabinoid Research Group, Institute of Protein Biochemistry, Consiglio Nazionale delle Ricerche, Naples, Italy; Thoracic Surgery Unit, Second University of Naples, Naples, Italy; Division of Allergy and Clinical Immunology, University of Salerno, Salerno, Italy; and Consiglio Nazionale delle Ricerche Institute of Experimental Endocrinology and Oncology "G. Salvatore," Naples, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Loffredo
authors.affiliation: Departments of *Translational Medical Sciences and Center for Basic and Clinical Immunology Research and Neuroscience, Reproductive and Odontostomatological Sciences, University of Naples Federico II, Naples, Italy; Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Naples, Italy; Endocannabinoid Research Group, Institute of Protein Biochemistry, Consiglio Nazionale delle Ricerche, Naples, Italy; Thoracic Surgery Unit, Second University of Naples, Naples, Italy; Division of Allergy and Clinical Immunology, University of Salerno, Salerno, Italy; and Consiglio Nazionale delle Ricerche Institute of Experimental Endocrinology and Oncology "G. Salvatore," Naples, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Borriello
authors.affiliation: Departments of *Translational Medical Sciences and Center for Basic and Clinical Immunology Research and Neuroscience, Reproductive and Odontostomatological Sciences, University of Naples Federico II, Naples, Italy; Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Naples, Italy; Endocannabinoid Research Group, Institute of Protein Biochemistry, Consiglio Nazionale delle Ricerche, Naples, Italy; Thoracic Surgery Unit, Second University of Naples, Naples, Italy; Division of Allergy and Clinical Immunology, University of Salerno, Salerno, Italy; and Consiglio Nazionale delle Ricerche Institute of Experimental Endocrinology and Oncology "G. Salvatore," Naples, Italy.
authors.forename: Fabio Arturo
authors.initials: FA
authors.lastname: Iannotti
authors.affiliation: Departments of *Translational Medical Sciences and Center for Basic and Clinical Immunology Research and Neuroscience, Reproductive and Odontostomatological Sciences, University of Naples Federico II, Naples, Italy; Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Naples, Italy; Endocannabinoid Research Group, Institute of Protein Biochemistry, Consiglio Nazionale delle Ricerche, Naples, Italy; Thoracic Surgery Unit, Second University of Naples, Naples, Italy; Division of Allergy and Clinical Immunology, University of Salerno, Salerno, Italy; and Consiglio Nazionale delle Ricerche Institute of Experimental Endocrinology and Oncology "G. Salvatore," Naples, Italy.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Piscitelli
authors.affiliation: Departments of *Translational Medical Sciences and Center for Basic and Clinical Immunology Research and Neuroscience, Reproductive and Odontostomatological Sciences, University of Naples Federico II, Naples, Italy; Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Naples, Italy; Endocannabinoid Research Group, Institute of Protein Biochemistry, Consiglio Nazionale delle Ricerche, Naples, Italy; Thoracic Surgery Unit, Second University of Naples, Naples, Italy; Division of Allergy and Clinical Immunology, University of Salerno, Salerno, Italy; and Consiglio Nazionale delle Ricerche Institute of Experimental Endocrinology and Oncology "G. Salvatore," Naples, Italy.
authors.forename: Pierangelo
authors.initials: P
authors.lastname: Orlando
authors.affiliation: Departments of *Translational Medical Sciences and Center for Basic and Clinical Immunology Research and Neuroscience, Reproductive and Odontostomatological Sciences, University of Naples Federico II, Naples, Italy; Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Naples, Italy; Endocannabinoid Research Group, Institute of Protein Biochemistry, Consiglio Nazionale delle Ricerche, Naples, Italy; Thoracic Surgery Unit, Second University of Naples, Naples, Italy; Division of Allergy and Clinical Immunology, University of Salerno, Salerno, Italy; and Consiglio Nazionale delle Ricerche Institute of Experimental Endocrinology and Oncology "G. Salvatore," Naples, Italy.
authors.forename: Agnese
authors.initials: A
authors.lastname: Secondo
authors.affiliation: Departments of *Translational Medical Sciences and Center for Basic and Clinical Immunology Research and Neuroscience, Reproductive and Odontostomatological Sciences, University of Naples Federico II, Naples, Italy; Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Naples, Italy; Endocannabinoid Research Group, Institute of Protein Biochemistry, Consiglio Nazionale delle Ricerche, Naples, Italy; Thoracic Surgery Unit, Second University of Naples, Naples, Italy; Division of Allergy and Clinical Immunology, University of Salerno, Salerno, Italy; and Consiglio Nazionale delle Ricerche Institute of Experimental Endocrinology and Oncology "G. Salvatore," Naples, Italy.
authors.forename: Francescopaolo
authors.initials: F
authors.lastname: Granata
authors.affiliation: Departments of *Translational Medical Sciences and Center for Basic and Clinical Immunology Research and Neuroscience, Reproductive and Odontostomatological Sciences, University of Naples Federico II, Naples, Italy; Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Naples, Italy; Endocannabinoid Research Group, Institute of Protein Biochemistry, Consiglio Nazionale delle Ricerche, Naples, Italy; Thoracic Surgery Unit, Second University of Naples, Naples, Italy; Division of Allergy and Clinical Immunology, University of Salerno, Salerno, Italy; and Consiglio Nazionale delle Ricerche Institute of Experimental Endocrinology and Oncology "G. Salvatore," Naples, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Lepore
authors.affiliation: Departments of *Translational Medical Sciences and Center for Basic and Clinical Immunology Research and Neuroscience, Reproductive and Odontostomatological Sciences, University of Naples Federico II, Naples, Italy; Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Naples, Italy; Endocannabinoid Research Group, Institute of Protein Biochemistry, Consiglio Nazionale delle Ricerche, Naples, Italy; Thoracic Surgery Unit, Second University of Naples, Naples, Italy; Division of Allergy and Clinical Immunology, University of Salerno, Salerno, Italy; and Consiglio Nazionale delle Ricerche Institute of Experimental Endocrinology and Oncology "G. Salvatore," Naples, Italy.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Fiorelli
authors.affiliation: Departments of *Translational Medical Sciences and Center for Basic and Clinical Immunology Research and Neuroscience, Reproductive and Odontostomatological Sciences, University of Naples Federico II, Naples, Italy; Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Naples, Italy; Endocannabinoid Research Group, Institute of Protein Biochemistry, Consiglio Nazionale delle Ricerche, Naples, Italy; Thoracic Surgery Unit, Second University of Naples, Naples, Italy; Division of Allergy and Clinical Immunology, University of Salerno, Salerno, Italy; and Consiglio Nazionale delle Ricerche Institute of Experimental Endocrinology and Oncology "G. Salvatore," Naples, Italy.
authors.forename: Gilda
authors.initials: G
authors.lastname: Varricchi
authors.affiliation: Departments of *Translational Medical Sciences and Center for Basic and Clinical Immunology Research and Neuroscience, Reproductive and Odontostomatological Sciences, University of Naples Federico II, Naples, Italy; Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Naples, Italy; Endocannabinoid Research Group, Institute of Protein Biochemistry, Consiglio Nazionale delle Ricerche, Naples, Italy; Thoracic Surgery Unit, Second University of Naples, Naples, Italy; Division of Allergy and Clinical Immunology, University of Salerno, Salerno, Italy; and Consiglio Nazionale delle Ricerche Institute of Experimental Endocrinology and Oncology "G. Salvatore," Naples, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Santini
authors.affiliation: Departments of *Translational Medical Sciences and Center for Basic and Clinical Immunology Research and Neuroscience, Reproductive and Odontostomatological Sciences, University of Naples Federico II, Naples, Italy; Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Naples, Italy; Endocannabinoid Research Group, Institute of Protein Biochemistry, Consiglio Nazionale delle Ricerche, Naples, Italy; Thoracic Surgery Unit, Second University of Naples, Naples, Italy; Division of Allergy and Clinical Immunology, University of Salerno, Salerno, Italy; and Consiglio Nazionale delle Ricerche Institute of Experimental Endocrinology and Oncology "G. Salvatore," Naples, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Triggiani
authors.affiliation: Departments of *Translational Medical Sciences and Center for Basic and Clinical Immunology Research and Neuroscience, Reproductive and Odontostomatological Sciences, University of Naples Federico II, Naples, Italy; Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Naples, Italy; Endocannabinoid Research Group, Institute of Protein Biochemistry, Consiglio Nazionale delle Ricerche, Naples, Italy; Thoracic Surgery Unit, Second University of Naples, Naples, Italy; Division of Allergy and Clinical Immunology, University of Salerno, Salerno, Italy; and Consiglio Nazionale delle Ricerche Institute of Experimental Endocrinology and Oncology "G. Salvatore," Naples, Italy marone@unina.it vdimarzo@icb.cnr.it.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
authors.affiliation: Departments of *Translational Medical Sciences and Center for Basic and Clinical Immunology Research and Neuroscience, Reproductive and Odontostomatological Sciences, University of Naples Federico II, Naples, Italy; Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Naples, Italy; Endocannabinoid Research Group, Institute of Protein Biochemistry, Consiglio Nazionale delle Ricerche, Naples, Italy; Thoracic Surgery Unit, Second University of Naples, Naples, Italy; Division of Allergy and Clinical Immunology, University of Salerno, Salerno, Italy; and Consiglio Nazionale delle Ricerche Institute of Experimental Endocrinology and Oncology "G. Salvatore," Naples, Italy marone@unina.it vdimarzo@icb.cnr.it.
authors.forename: Gianni
authors.initials: G
authors.lastname: Marone
mesh_terms: D002186:Cannabinoids / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D043884:Receptor, Cannabinoid, CB1 / Q000096:biosynthesis*; D043885:Receptor, Cannabinoid, CB2 / Q000096:biosynthesis*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*; D042582:Vascular Endothelial Growth Factor C / Q000096:biosynthesis*
chemical_list: C588309:CNR2 protein, human; D002186:Cannabinoids; C508600:IL6 protein, human; D015850:Interleukin-6; D008070:Lipopolysaccharides; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C467484:VEGFA protein, human; C467486:VEGFC protein, human; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; C432747:1,1-dimethylbutyl-1-deoxy-Delta(9)-THC
keywords: cannabinoid receptors; endocannabinoids; lung cancer