Anti-inflammatory effects of nicotinic acid in adipocytes demonstrated by suppression of fractalkine, RANTES, and MCP-1 and upregulation of adiponectin.
OBJECTIVE
A major site of action for the atheroprotective drug nicotinic acid (NA) is adipose tissue, via the G-protein-coupled receptor, GPR109A. Since, adipose tissue is an active secretory organ that contributes both positively and negatively to systemic inflammatory processes associated with cardiovascular disease, we hypothesized that NA would act directly upon adipocytes to alter the expression of pro-inflammatory chemokines, and the anti-inflammatory adipokine adiponectin.


RESULTS
TNF-alpha treatment (1.0ng/mL) of 3T3-L1 adipocytes resulted in an increase in gene expression of fractalkine (9+/-3.3-fold, P<0.01); monocyte chemoattractant protein-1 (MCP-1) (24+/-1.2-fold, P<0.001), 'regulated upon activation, normal T cell expressed and secreted' (RANTES) (500+/-55-fold, P<0.001) and inducible nitric oxide synthase (iNOS) (200+/-70-fold, P<0.05). The addition of NA (10(-4)M) to TNF-alpha-treated adipocytes attenuated expression of fractalkine (50+/-12%, P<0.01); MCP-1 (50+/-6%, P<0.01), RANTES (70+/-3%, P<0.01) and iNOS (60+/-16%). This pattern was mirrored in protein released from the adipocytes into the surrounding media. The effect on gene expression was neutralised by pre-treatment with pertussis toxin. NA attenuated macrophage chemotaxis (by 27+/-3.5%, P<0.001) towards adipocyte conditioned media. By contrast, NA, (10(-6)-10(-3)M) increased, in a dose-dependent manner, mRNA of the atheroprotective hormone adiponectin (3-5-fold n=6, P<0.01).


CONCLUSIONS
NA suppresses pro-atherogenic chemokines and upregulates the atheroprotective adiponectin through a G-protein-coupled pathway. Since adipose tissue has the potential to contribute to both systemic and local (perivascular) inflammation associated with atherosclerosis our results suggest a new "pleiotropic" role for NA.
Department of Cardiovascular Medicine, University of Oxford, Oxford, United Kingdom.
Janet E
JE
Digby
Eileen
E
McNeill
Oliver J
OJ
Dyar
Vincent
V
Lam
David R
DR
Greaves
Robin P
RP
Choudhury
D016475:3T3 Cells; D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism; D052242:Adiponectin / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D050197:Atherosclerosis / Q000378:metabolism / Q000517:prevention & control*; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D018946:Chemokine CCL5 / Q000037:antagonists & inhibitors / Q000378:metabolism; D054428:Chemokine CX3CL1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000378:metabolism; D051379:Mice; D009525:Niacin / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation
D052242:Adiponectin; D000894:Anti-Inflammatory Agents, Non-Steroidal; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D054428:Chemokine CX3CL1; D017077:Culture Media, Conditioned; D043562:Receptors, G-Protein-Coupled; D014409:Tumor Necrosis Factor-alpha; D009525:Niacin