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LANGERHANS CELLS RELEASE PROSTAGLANDIN D2 IN RESPONSE TO NICOTINIC ACID.

Maciejewski-Lenoir, D., Richman, J., Hakak, Y., Gaidarov, I., Behan, D., and Connolly, D. Arena Pharmaceuticals Inc., San Diego, CA.
Abstract

This study by researchers at Arena Pharmaceuticals demonstrated that MatTek’s Human Dendritic Cells can be used to identify the mechanism of a drug’s in vivo adverse side effects. Nicotinic acid, used for atherosclerosis treatment, has an adverse effect of skin flushing. The flushing mechanism, thought to be caused by the release of prostaglandin D2 (PGD2), is not well understood. In this study, researchers at Arena Pharmaceuticals attempted to identify which cells mediate the flushing effect. Nicotinic acid receptor (GPR109A) gene expression was assessed in various tissues and cell lines. Cells expressing GPR109A mRNA were further assayed for PGD2 release in response to nicotinic acid. Of all samples, only skin was able to release PGD2 upon stimulation with nicotinic acid. The responsive cells were localized to the epidermis, and immunocytochemical studies revealed the presence of GPR109A on epidermal Langerhans cells. CD34+ cells isolated from human blood and differentiated into Langerhans cells (hLC-L) from MatTek Corp. also showed GPR109A expression. IFN ã treatment increased both mRNA and plasma membrane expression of GPR109A. IFN ã-stimulated hLC-Ls released PGD2 in response to nicotinic acid in a dose-dependant manner (effector concentration for half-maximum response=1.2mM±0.7). Acifran, a structurally distinct GPR109A ligand, also increased PGD2 release, whereas isonicotinic acid, a nicotinic acid analog with low affinity for GPR109A, had no effect. These results suggest that nicotinic acid mediates its flushing side effect by interacting with GPR109A on skin Langerhans cells, resulting in release of PGD2.

Keywords

4’,6 diamidine-2-phenylindolc (DAPL), Acifran, Atherosclerosis, CD1a, CD34+, Flushing response, GPR109A protein expression, Immunocytochemical analysis, Isonicotinic acid, Langerhan Cells, MHC class II surface markers, MRNA, Messenger RNA (mRNA), Nicotinic Acid, Nicotinic acid receptor (GPR109A), PGD2, Prostaglandin D2, RT-PCR analysis, Skin flushing, Vasodilatation, mRNA

Materials Tested

Aceficacid acid, Acifran, Cell line, GPR109A, IFN-gamma, Indomethacin, Isonicotinic acid, Niacin, Nicotinic acid

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