title: The role of HCA2 (GPR109A) in regulating macrophage function.
abstract: We investigated the novel role of HCA2 (GPR109A) and its ligand nicotinic acid in regulating macrophage function. Hca2 expression in the RAW264.7 murine macrophage cell line is strongly induced by LPS treatment and correlates with the expression of TNF-α. Treatment with 300 μM nicotinic acid (reported EC50 3 μM, peak plasma concentration 50-300 μM), significantly inhibited TNF-α, IL-6, IL-12p40, and IL-1β production (P<0.05) in LPS (1 ng/ml)-stimulated wild-type murine bone marrow-derived macrophages (BMMs) but failed to do so in Hca2(-/-) BMMs. Treatment with nicotinic acid reduced nuclear factor κB (NF-κB) activation levels by 43% (P<0.03) in wild-type BMMs 6 h after LPS stimulation but not in Hca2(-/-) BMMs. Nicotinic acid significantly inhibited wild-type BMM chemotaxis (P<0.001), but had no effect on the chemotaxis of Hca2(-/-) BMMs. A significant increase in low-density lipoprotein uptake by both wild-type (P<0.006) and Hca2(-/-) BMMs (P<0.03) in response to LPS was observed, which was significantly suppressed by nicotinic acid in wild-type BMMs (P<0.04) but not in Hca2(-/-) BMMs. Our results suggest that the nicotinic acid-HCA2 axis is a novel negative regulator of macrophage activation.
authors.affiliation: 2Division of Nephrology, 330 Brookline Ave., E/RN 304, Boston, MA 02215, USA. kzandi@bidmc.harvard.edu.
authors.forename: Kambiz
authors.initials: K
authors.lastname: Zandi-Nejad
authors.forename: Ayumi
authors.initials: A
authors.lastname: Takakura
authors.forename: Mollie
authors.initials: M
authors.lastname: Jurewicz
authors.forename: Anil K
authors.initials: AK
authors.lastname: Chandraker
authors.forename: Stefan
authors.initials: S
authors.lastname: Offermanns
authors.forename: David
authors.initials: D
authors.lastname: Mount
authors.forename: Reza
authors.initials: R
authors.lastname: Abdi
mesh_terms: D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D045744:Cell Line, Tumor; D002633:Chemotaxis / Q000187:drug effects; D007378:Interleukins / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000378:metabolism; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009525:Niacin / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: C473652:Hcar2 protein, mouse; D007378:Interleukins; D008070:Lipopolysaccharides; D008077:Lipoproteins, LDL; D016328:NF-kappa B; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic; D014409:Tumor Necrosis Factor-alpha; D009525:Niacin
keywords: HM74A; PUMA-G; inflammation; nicotinic acid