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4-Hydroxynonenal-induced GPR109A (HCA2 receptor) activation elicits bipolar responses, G?i -mediated anti-inflammatory effects and G?? -mediated cell death.

ABSTRACT: BACKGROUND AND PURPOSE:In this study, we examined the possibility that 4-hydroxynonenal (4-HNE) acting as a ligand for the HCA2 receptor (GPR109A) elicits both anti-inflammatory and cell death responses. EXPERIMENTAL APPROACH:Agonistic activity of 4-HNE was determined by observing the inhibition of cAMP generation in CHO-K1-GPR109A-Gi cell line, using surface plasmon resonance (SPR) binding and competition binding assays with [3 H]-niacin. 4-HNE-mediated signalling pathways and cellular responses were investigated in cells expressing GPR109A and those not expressing these receptors. KEY RESULTS:Agonistic activity of 4-HNE was stronger than that of niacin or 3-OHBA at inhibiting forskolin-induced cAMP production and SPR binding affinity. In ARPE-19 and CCD-841 cells, activation of GPR109A by high concentrations of the agonists 4-HNE (?10 ?M), niacin (?1000 ?M) and 3-OHBA (?1000 ?M) induced apoptosis accompanied by elevated Ca2+ and superoxide levels. This 4-HNE-induced cell death was blocked by knockdown of GPR109A or NOX4 genes, or treatment with chemical inhibitors of G?? (gallein), intracellular Ca2+ (BAPTA-AM), NOX4 (VAS2870) and JNK (SP600125), but not by the cAMP analogue 8-CPT-cAMP. By contrast, low concentrations of 4-HNE, niacin and 3-OHBA down-regulated the expression of pro-inflammatory cytokines IL-6 and IL-8. These 4-HNE-induced inhibitory effects were blocked by a cAMP analogue but not by inhibitors of G?? -downstream signalling molecules. CONCLUSIONS AND IMPLICATIONS:These results revealed that 4-HNE is a strong agonist for GPR109A that induces G?i -dependent anti-inflammatory and G?? -dependent cell death responses. Moreover, the findings indicate that specific intracellular signalling molecules, but not GPR109A, can serve as therapeutic targets to block 4-HNE-induced cell death.

SUBMITTER: Gautam J

PROVIDER: S-EPMC6003634 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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4-Hydroxynonenal-induced GPR109A (HCA<sub>2</sub> receptor) activation elicits bipolar responses, G<sub>αi</sub> -mediated anti-inflammatory effects and G<sub>βγ</sub> -mediated cell death.

Gautam Jaya J Banskota Suhrid S Shah Sajita S Jee Jun-Goo JG Kwon Eunju E Wang Ying Y Kim Dong Young DY Chang Hyun Wook HW Kim Jung-Ae JA

British journal of pharmacology 20180522 13

<h4>Background and purpose</h4>In this study, we examined the possibility that 4-hydroxynonenal (4-HNE) acting as a ligand for the HCA<sub>2</sub> receptor (GPR109A) elicits both anti-inflammatory and cell death responses.<h4>Experimental approach</h4>Agonistic activity of 4-HNE was determined by observing the inhibition of cAMP generation in CHO-K1-GPR109A-G<sub>i</sub> cell line, using surface plasmon resonance (SPR) binding and competition binding assays with [<sup>3</sup> H]-niacin. 4-HNE-me ...[more]

PMID: 29473951

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Project description:Nicotinic acid (NA) treatment has been associated with benefits in atherosclerosis that are usually attributed to effects on plasma lipoproteins. The NA receptor GPR109A is expressed in monocytes and macrophages, suggesting a possible additional role for NA in modulating function of these immune cells. We hypothesize that NA has the potential to act directly on monocytes to alter mediators of inflammation that may contribute to its antiatherogenic effects in vivo.In human monocytes activated by Toll-like receptor (TLR)-4 agonist lipopolysaccharide, NA reduced secretion of proinflammatory mediators: TNF-? (by 49.2±4.5%); interleukin-6 (by 56.2±2.8%), and monocyte chemoattractant protein-1 (by 43.2±3.1%) (P<0.01). In TLR2 agonist, heat-killed Listeria monocytogenes-activated human monocytes, NA reduced secretion of TNF-? (by 48.6±7.1%), interleukin-6 (by 60.9±1.6%), and monocyte chemoattractant protein-1 (by 59.3±5.3%) (P<0.01; n=7). Knockdown of GPR109A by siRNA resulted in a loss of this anti-inflammatory effect in THP-1 monocytes. However, inhibition of prostaglandin D2 receptor by MK0524 or COX2 by NS398 did not alter the anti-inflammatory effects of NA observed in activated human monocytes. Preincubation of THP-1 monocytes with NA 0.1 mmol/L reduced phosphorylated IKK? by 42±2% (P<0.001) IKB-? by 54±14% (P<0.01). Accumulation of nuclear p65 NF-?B in response to lipopolysaccharide treatment was also profoundly inhibited, by 89±1.3% (n=4; P<0.01). NA potently inhibited monocyte adhesion to activated HUVEC, and VCAM, mediated by the integrin, very late antigen 4. Monocyte chemotaxis was also significantly reduced (by 45.7±1.2%; P<0.001).NA displays a range of effects that are lipoprotein-independent and potentially antiatherogenic. These effects are mediated by GPR109A and are independent of prostaglandin pathways. They suggest a rationale for treatment with NA that is not dependent on levels of plasma cholesterol and possible applications beyond the treatment of dyslipidemia.

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Dataset Information

4-Hydroxynonenal-induced GPR109A (HCA2 receptor) activation elicits bipolar responses, G?i -mediated anti-inflammatory effects and G?? -mediated cell death.

Publications

4-Hydroxynonenal-induced GPR109A (HCA<sub>2</sub> receptor) activation elicits bipolar responses, G<sub>αi</sub> -mediated anti-inflammatory effects and G<sub>βγ</sub> -mediated cell death.

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