Langerhans Cells Release Prostaglandin D2 in Response to Nicotinic Acid

Abstract

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).

Nicotinic Acid Receptor Agonists Differentially Activate Downstream Effectors

“…Recent work examining the mechanism of niacin-induced flushing has revealed that it is mediated by GPR109A (16) and requires the release of PGD 2 and activation of DP1 receptors in the skin (18) and, finally, that the PGD 2 release is mediated by epidermal Langerhans cells (17,19). Based on the results shown herein we would speculate that GPR109A agonists activate a MAP kinase-mediated release of PGD 2 from Langerhans cells, leading to the cutaneous vasodilation responsible for the flushing response.…”

“…Recent work has begun to elucidate the mechanism by which nicotinic acid induces flushing (16 -19). GPR109A has been shown to mediate nicotinic acid-induced flushing through release of prostaglandin D2 (PGD 2 ) and involves the activation of the DP1 receptor and possibly a PGE 2 receptor (EP2 or EP4) (16, 18) Recent work has further supported the hypothesis that it is GPR109A receptors on Langerhans cells in the skin that mediate nicotinic acid-induced flushing through generation of PGD 2 (17,19).…”

“…Recent work has begun to elucidate the mechanism by which nicotinic acid induces flushing (16 -19). GPR109A has been shown to mediate nicotinic acid-induced flushing through release of prostaglandin D2 (PGD 2 ) and involves the activation of the DP1 receptor and possibly a PGE 2 receptor (EP2 or EP4) (16, 18) Recent work has further supported the hypothesis that it is GPR109A receptors on Langerhans cells in the skin that mediate nicotinic acid-induced flushing through generation of PGD 2 (17,19).A series of pyrazole derivatives have been reported in the literature that act as partial agonists for the nicotinic acid receptor (20). The authors postulate that tissue selectivity, commonly observed with partial agonists, could be useful in pre-* The costs of publication of this article were defrayed in part by the payment of page charges.…”

“…50 l of RPMI containing 1 mM nicotinic acid, 10 M indomethacin, or vehicle were added to each well and the cells were further incubated for 30 min and treated as described in Ref. 19.…”

Phospholipid, arachidonate and eicosanoid signaling in schizophrenia

“…Formation of AA is the rate-limiting step in the biosynthesis of the vasodilatory PGD 2 and E2 (PGE 2 ) (Murakami and Kudo 2004) These prostaglandins bind to specific prostanoid receptors on vascular smooth muscle within the skin. Activation of prostanoid receptors dilates cutaneous blood vessels (Lai et al, 2007), and a visible skin flush arises from the ensuing increased blood flow (Benyó et al, 2005;Maciejewski-Lenoir et al, 2006;Morrow et al, 1989Morrow et al, , 1992.…”