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Niacin, as an antidyslipidemic drug, elicits a strong flushing response by release of prostaglandin (PG) D 2 However, whether niacin is beneficial for inflammatory bowel disease (IBD) remains unclear. Here, we observed niacin administration-enhanced PGD 2 production in colon tissues in dextran sulfate sodium (DSS)-challenged mice, and protected mice against DSS or 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in D prostanoid receptor 1 (DP1)-dependent manner. Specific ablation of DP1 receptor in vascular endothelial cells, colonic epithelium, and myeloid cells augmented DSS/TNBS-induced colitis in mice through increasing vascular permeability, promoting apoptosis of epithelial cells, and stimulating pro-inflammatory cytokine secretion of macrophages, respectively. Niacin treatment improved vascular permeability, reduced apoptotic epithelial cells, promoted epithelial cell update, and suppressed pro-inflammatory gene expression of macrophages. Moreover, treatment with niacin-containing retention enema effectively promoted UC clinical remission and mucosal healing in patients with moderately active disease. Therefore, niacin displayed multiple beneficial effects on DSS/TNBS-induced colitis in mice by activation of PGD 2 /DP1 axis. The potential efficacy of niacin in management of IBD warrants further investigation., (© 2017 The Authors. Published under the terms of the CC BY 4.0 license.)

Niacin is a well established drug used to lower cholesterol and prevent cardiovascular disease events. However, niacin also causes cutaneous flushing side effects due to release of the proresolution mediator prostaglandin D 2 (PGD 2 ). Recent randomized clinical trials have demonstrated that addition of niacin with laropiprant [a PGD 2 receptor subtype 1 (DP1) blocker] to statin-based therapies does not significantly decrease the risk of cardiovascular disease events, but increases the risk of serious adverse events. Here, we tested whether, and how, niacin beneficial effects on myocardial ischemia require the activation of the PGD 2 /DP1 axis. Myocardial infarction (MI) was reproduced by ligation of the left anterior descending branch of the coronary artery in mice. We found that niacin increased PGD 2 release in macrophages and shifted macrophages to M2 polarization both in vitro and in vivo by activation of DP1 and accelerated inflammation resolution in zymosan-induced peritonitis in mice. Moreover, niacin treatment facilitated wound healing and improved cardiac function after MI through DP1-mediated M2 bias and timely resolution of inflammation in infarcted hearts. In addition, we found that niacin intake also stimulated M2 polarization of peripheral monocytes in humans. Collectively, niacin promoted cardiac functional recovery after ischemic myocardial infarction through DP1-mediated M2 polarization and timely resolution of inflammation in hearts. These results indicated that DP1 inhibition may attenuate the cardiovascular benefits of niacin., (Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.)

The kinetic participation of macrophages is critical for inflammatory resolution and recovery from myocardial infarction (MI), particularly with respect to the transition from the M1 to the M2 phenotype; however, the underlying mechanisms are poorly understood. In this study, we found that the deletion of prostaglandin (PG) D2 receptor subtype 1 (DP1) in macrophages retarded M2 polarization, antiinflammatory cytokine production, and resolution in different inflammatory models, including the MI model. DP1 deletion up-regulated proinflammatory genes expression via JAK2/STAT1 signaling in macrophages, whereas its activation facilitated binding of the separated PKA regulatory IIα subunit (PRKAR2A) to the transmembrane domain of IFN-γ receptor, suppressed JAK2-STAT1 axis-mediated M1 polarization, and promoted resolution. PRKAR2A deficiency attenuated DP1 activation-mediated M2 polarization and resolution of inflammation. Collectively, PGD2-DP1 axis-induced M2 polarization facilitates resolution of inflammation through the PRKAR2A-mediated suppression of JAK2/STAT1 signaling. These observations indicate that macrophage DP1 activation represents a promising strategy in the management of inflammation-associated diseases, including post-MI healing., (© 2016 Kong et al.)

The chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) receptor, a G protein-coupled receptor that mediates chemotaxis of inflammatory cells in response to prostaglandin D2 (PGD2), is hypothesized to play a role in Th2-mediated allergic disease. In addition to PGD2, CRTH2 can be activated by indomethacin, a nonselective cyclooxygenase inhibitor and widely used nonsteroidal anti-inflammatory drug (NSAID). To evaluate the structural features that confer CRTH2 binding selectivity, structure-activity relationship analysis of arylacetic acid class NSAIDs as CRTH2 receptor ligands was performed. Indomethacin, sulindac sulfide, and zomepirac displaced [3H]PGD2 binding at the mouse CRTH2 receptor (mCRTH2) with comparable affinity (Ki = 1.5 +/- 0.1, 2.5 +/- 0.4, and 3.3 +/- 0.3 microM, respectively). The indomethacin metabolite 5'-O-desmethyl indomethacin (5'-DMI) possessed binding affinity similar to indomethacin; however, elimination of the 2-methyl substituent on the indole ring resulted in a 10-fold decrease in binding affinity. No binding was detected for indole acetic acid and indole derivatives such as tryptophan, serotonin, and 5-hydroxy indole acetic acid, demonstrating the importance of the N-acyl moiety of indomethacin. Neutral derivatives of indomethacin also failed to bind to mCRTH2, suggesting that the negatively charged carboxylate moiety participates in a key ligand-receptor interaction. Despite similar binding affinities, NSAID-type mCRTH2 ligands exhibited variable potencies as mCRTH2 agonists. Sulindac sulfide and 5'-DMI inhibited intracellular cyclic AMP ([cAMP]i) generation and stimulated cell migration comparable with indomethacin. In contrast, zomepirac did not inhibit [cAMP]i generation or stimulate cell migration but weakly antagonized the effects of indomethacin on [cAMP]i. Together, these results reveal structural features of arylacetic acid NSAIDs that may be exploited for the development of selective CRTH2 ligands.

Prostaglandin D2 (PGD2), the predominant prostanoid produced by activated mast cells, is implicated in a variety of allergic diseases. PGD2 exerts its effects through two G-protein coupled receptors, DP and CRTH2. PGD2 mediates chemotaxis of eosinophils, basophils, and Th2 cells via CRTH2-evoked signaling, suggesting a role for this receptor in allergic disease. To characterize the mouse CRTH2 ortholog (mCRTH2), we amplified the mCRTH2 receptor gene and expressed it in HEK293 cells. Saturation ligand binding isotherms demonstrated high-affinity binding of [3H]PGD2, with a Kd of 8.8 +/- 0.8 nM. Competition binding assays with a panel unlabeled prostanoids demonstrated an order of affinity of 13,14-dihydro-15-keto-PGD2 (DK-PGD2) >or= 15-deoxy-Delta12,14-PGJ2 (15d-PGJ2) >or= PGD2 >or= PGJ2. [3H]PGD2 binding was also displaced by the nonsteroidal anti-inflammatory drug indomethacin, with a Ki value of 1.04 +/- 0.13 microM. No [3H]PGD2 displacement was detected using fluribrofen, ibuprofen, or aspirin as competitors at concentrations of up to 30 microM. PGD2, DK-PGD2, 15d-PGJ2, and indomethacin each inhibited intracellular cAMP generation in stable transfectant ER293/mCRTH2 cells through a pertussis toxin (PTX) sensitive pathway, consistent with mCRTH2 coupling to a Gi heterotrimeric G-protein. Activation of mCRTH2 elicited chemotaxis of ER293/mCRTH2 cells in response to PGD2, indomethacin, and 15d-PGJ2. mCRTH2-dependent chemotaxis was inhibited by PTX and wortmannin, indicating dependence on Gi and PI 3-kinase signal transduction pathways. These data provide the first pharmacological and functional characterization of the mouse CRTH2 receptor.

Peroxisome proliferator-activated receptor-gamma (PPAR gamma) is a nuclear transcription factor and the pharmacological target for antidiabetic thiazolidinediones (TZDs). TZDs ameliorate diabetic nephropathy and have direct effects on cultured mesangial cells (MCs); however, in situ hybridization failed to detect expression of PPAR gamma in glomeruli in vivo. The purpose of this study was to determine whether PPAR gamma is expressed in renal glomeruli. Two rabbit PPAR gamma isoforms were cloned. Nuclease protection assays demonstrate that both PPAR gamma isoforms are expressed in freshly isolated glomeruli. Treatment of rabbits with the TZD troglitazone selectively induced expression of an endogenous PPAR gamma target gene, adipocyte fatty acid-binding protein (A-FABP), in renal glomerular cells and renal medullary microvascular endothelial cells, demonstrated by both in situ hybridization and immunostain. Troglitazone also dramatically increased A-FABP expression in cultured MCs. Constitutive PPAR gamma expression was detected in cultured rabbit MCs. Endogenous MC PPAR gamma can also drive PPAR gamma reporter. Troglitazone and 15-deoxy-Delta 12,14 prostaglandin J(2) at low concentrations reduced mesangial cell [(3)H]thymidine incorporation without affecting viability. These data suggest that constitutive PPAR gamma activity exists in renal glomeruli in vivo and could provide a pharmacological target to directly modulate glomerular injury.