Langerhans cells release prostaglandin D2 in response to nicotinic acid.
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 D(2) (PGD(2)), is not well understood. We aimed 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 PGD(2) release in response to nicotinic acid. Of all samples, only skin was able to release PGD(2) 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) also showed GPR109A expression. IFNgamma treatment increased both mRNA and plasma membrane expression of GPR109A. IFNgamma-stimulated hLC-Ls released PGD(2) in response to nicotinic acid in a dose-dependant manner (effector concentration for half-maximum response=1.2 mM+/-0.7). Acifran, a structurally distinct GPR109A ligand, also increased PGD(2) 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 PGD(2).
Maciejewski-Lenoir
Dominique
D
Arena Pharmaceuticals Inc., San Diego, California 92121, USA. dlenoir@arenapharm.com
Richman
Jeremy G
JG
Hakak
Yaron
Y
Gaidarov
Ibragim
I
Behan
Dominic P
DP
Connolly
Daniel T
DT
D000818:Animals; D002478:Cells, Cultured; D005483:Flushing / Q000139:chemically induced*; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D007801:Langerhans Cells / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009525:Niacin / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis; D015230:Prostaglandin D2 / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000378:metabolism; D014018:Tissue Distribution
C530636:HCAR2 protein, human; C473653:HCAR3 protein, human; C473652:Hcar2 protein, mouse; D000960:Hypolipidemic Agents; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic; D009525:Niacin; D015230:Prostaglandin D2