Mol Pharmacol. 2006 Sep 29; [Epub ahead of print]
Nicotinic acid-induced flushing is mediated by activation of epidermal Langerhans cells.
Benyo Z, Gille A, Bennett C, Clausen BE, Offermanns S.
University of Heidelberg.
The anti-dyslipidemic drug nicotinic acid (niacin) has been used for decades. One of the major problems of the therapeutical use of nicotinic acid is a strong cutaneous vasodilation called flushing which develops in almost every patient taking nicotinic acid. Nicotinic acid-induced flushing has been shown to be mediated by the nicotinic acid receptor GPR109A and to involve the formation of vasodilatory prostanoids. However, the cellular mechanisms underlying this acute effect are unknown. Here we show that epidermal Langerhans cells are essential for the cutaneous flushing response induced by nicotinic acid. Langerhans cells respond with an increase in [Ca(2+)]i to nicotinic acid and express prostanoid synthases required for the formation of the vasodilatory prostanoids prostaglandin E2 and prostaglandin D2. Depletion of epidermal Langerhans cells but not of macrophages or dendritic cells abrogates nicotinic acid induced flushing. These data unexpectedly identify epidermal Langerhans cells as essential mediators of nicotinic acid induced flushing and may help to generate new strategies to suppress the unwanted effects of nicotinic acid. In addition, our results suggest that Langerhans cells besides their immunological roles are also involved in the local regulation of dermal blood flow.
J Invest Dermatol. 2006 Sep 28; [Epub ahead of print]
Langerhans Cells Release Prostaglandin D(2) in Response to Nicotinic Acid.
Maciejewski-Lenoir D, Richman JG, Hakak Y, Gaidarov I, Behan DP, Connolly DT.
1Arena Pharmaceuticals Inc., San Diego, California, USA.
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).Journal of Investigative Dermatology advance online publication, 28 September 2006; doi:10.1038/sj.jid.5700586. |
