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Nicotinic acid– and monomethyl fumarate–induced flushing involves GPR109A expressed by keratinocytes and COX-2–dependent prostanoid formation in mice
Julien Hanson, … , Angela Wirth, Stefan Offermanns
Julien Hanson, … , Angela Wirth, Stefan Offermanns
Published July 26, 2010
Citation Information: J Clin Invest. 2010;120(8):2910-2919. https://doi.org/10.1172/JCI42273.
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Nicotinic acid– and monomethyl fumarate–induced flushing involves GPR109A expressed by keratinocytes and COX-2–dependent prostanoid formation in mice

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Abstract

The antidyslipidemic drug nicotinic acid and the antipsoriatic drug monomethyl fumarate induce cutaneous flushing through activation of G protein–coupled receptor 109A (GPR109A). Flushing is a troublesome side effect of nicotinic acid, but may be a direct reflection of the wanted effects of monomethyl fumarate. Here we analyzed the mechanisms underlying GPR109A-mediated flushing and show that both Langerhans cells and keratinocytes express GPR109A in mice. Using cell ablation approaches and transgenic cell type–specific GPR109A expression in Gpr109a–/– mice, we have provided evidence that the early phase of flushing depends on GPR109A expressed on Langerhans cells, whereas the late phase is mediated by GPR109A expressed on keratinocytes. Interestingly, the first phase of flushing was blocked by a selective cyclooxygenase-1 (COX-1) inhibitor, and the late phase was sensitive to a selective COX-2 inhibitor. Both monomethyl fumarate and nicotinic acid induced PGE2 formation in isolated keratinocytes through activation of GPR109A and COX-2. Thus, the early and late phases of the GPR109A-mediated cutaneous flushing reaction involve different epidermal cell types and prostanoid-forming enzymes. These data will help to guide new efficient approaches to mitigate nicotinic acid–induced flushing and may help to exploit the potential antipsoriatic effects of GPR109A agonists in the skin.

Authors

Julien Hanson, Andreas Gille, Sabrina Zwykiel, Martina Lukasova, Björn E. Clausen, Kashan Ahmed, Sorin Tunaru, Angela Wirth, Stefan Offermanns

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Figure 1

Keratinocytes express GPR109A.

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Keratinocytes express GPR109A.
(A) Scheme of the Gpr109a reporter BAC tr...
(A) Scheme of the Gpr109a reporter BAC transgene. (B and C) Gpr109a expression in the epidermis. Shown are sections through the epidermis (B) and en face views of the epidermis (C) from WT and Gpr109amRFP mice. Cell nuclei were stained with DAPI, and keratinocytes and Langerhans cells were visualized by immunofluorescence labeling with antibodies directed against MHC-II (B) and cytokeratin (C). mRFP fluorescence was detected in parallel to visualize GPR109A expression. Dotted line denotes the basal membrane. Sb, stratum basale; Sg, stratum granulosum; Ss, stratum spinosum. Scale bars: 10 μm (B); 20 μm (C). (D) RT-PCR to analyze Gpr109a expression in human and mouse keratinocytes. The cDNA synthesis reaction was performed in the absence or presence of RT. (E) Effects of 100 μM nicotinic acid (NA) and 10% FBS on ERK1/2 phosphorylation in keratinocytes prepared from WT or Gpr109a–/– mice, analyzed with an antibody recognizing phosphorylated ERK1/2. In parallel, the total amount of ERK1/2 was determined. (F and G) Effect of 100 μM NA on free [Ca2+]i in Fura-2–loaded keratinocytes from WT (F) and Gpr109a–/– (G) mice. ATP (100 μM) was applied as a positive control.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 28 patents
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