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J Leukoc Biol. 2016 Apr;99(4):531-40. doi: 10.1189/jlb.3HI1214-584R. Epub 2015 Oct 14.

Human lung-resident macrophages express CB1 and CB2 receptors whose activation inhibits the release of angiogenic and lymphangiogenic factors.

Author information

1
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.
2
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.

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.

KEYWORDS:

cannabinoid receptors; endocannabinoids; lung cancer

PMID:
26467187
PMCID:
PMC4787289
DOI:
10.1189/jlb.3HI1214-584R
[Indexed for MEDLINE]
Free PMC Article

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