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Antihistamines Suppress Upregulation of Histidine Decarboxylase Gene

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Antihistamines Suppress Upregulation of Histidine Decarboxylase Gene JPHS202_proof ■ 17 February 2016 ■ 1/7 Journal of Pharmacological Sciences xxx (2016) 1e7 55 HOSTED BY Contents lists available at ScienceDirect 56 57 Journal of Pharmacological Sciences 58 59 60 journal homepage: www.elsevier.com/locate/jphs 61 62 63 Full paper 64 65 1 Antihistamines suppress upregulation of histidine decarboxylase gene 66 2 fi 67 3 expression with potencies different from their binding af nities for 68 4 histamine H receptor in toluene 2,4-diisocyanate-sensitized rats 69 5 1 70 6 a, *, 3 a, 1, 3 b a, 1 71 7 Q8 Hiroyuki Mizuguchi , Asish K. Das , Kazutaka Maeyama , Shrabanti Dev , 72 a, 2 c c d 8 Masum Shahriar , Yoshiaki Kitamura , Noriaki Takeda , Hiroyuki Fukui 73 9 a Department of Molecular Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Sho-machi, Tokushima 770-8505, Japan 74 10 b Division of Pharmacology, Department of Integrated Basic Medical Science, Ehime University School of Medicine, Toon 791-0295, Japan 75 11 c Department of Otolaryngology, Institute of Biomedical Sciences, Tokushima University Graduate School, Kuramoto, Tokushima 770-8503, Japan 76 d 12 Department of Molecular Studies for Incurable Diseases, Institute of Biomedical Sciences, Tokushima University Graduate School, Kuramoto, Tokushima 77 770-8503, Japan 13 78 14 79 15 80 article info abstract 16 81 17 82 18 Article history: Antihistamines inhibit histamine signaling by blocking histamine H1 receptor (H1R) or suppressing H1R Received 7 September 2015 83 19 signaling as inverse agonists. The H1R gene is upregulated in patients with pollinosis, and its expression Received in revised form level is correlated with the severity of nasal symptoms. Here, we show that antihistamine suppressed 84 20 1 February 2016 upregulation of histidine decarboxylase (HDC) mRNA expression in patients with pollinosis, and its 85 21 Accepted 4 February 2016 expression level was correlated with that of H1R mRNA. Certain antihistamines, including mepyramine 86 Available online xxx 22 and diphenhydramine, suppress toluene-2,4-diisocyanate (TDI)-induced upregulation of HDC gene 87 23 expression and increase HDC activity in TDI-sensitized rats. However, d-chlorpheniramine did not 88 24 Keywords: Allergy demonstrate any effect. The potencies of antihistamine suppressive effects on HDC mRNA elevation were 89 fi 25 Antihistamines different from their H1R receptor binding af nities. In TDI-sensitized rats, the potencies of antihistamine 90 26 Gene expression inhibitory effects on sneezing in the early phase were related to H1R binding. In contrast, the potencies of 91 27 Histamine signaling their inhibitory effects on sneezing in the late phase were correlated with those of suppressive effects on 92 Histidine decarboxylase HDC mRNA elevation. Data suggest that in addition to the antihistaminic and inverse agonistic activities, 28 93 certain antihistamines possess additional properties unrelated to receptor binding and alleviate nasal 29 94 30 symptoms in the late phase by inhibiting synthesis and release of histamine by suppressing HDC gene transcription. 95 31 © 2016 Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society. This is an 96 32 open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 97 33 98 34 99 35 100 36 101 1. Introduction 37 102 38 103 Pollinosis, a seasonal allergic rhinitis, affects approximately 30% 39 104 of the Japanese population (1). Histamine plays important roles in 40 105 the pathogenesis of allergic rhinitis; its action is mainly mediated 41 Abbreviations: DEPC, diethylpyrocarbonate; PCA, perchloric acid; GAPDH, glyc- 106 eraldehyde-3-phosphate dehydrogenase; H1R, histamine H receptor; HDC, histi- through the histamine H1 receptor (H1R). Antihistamines act as 42 1 107 dine decarboxylase; IL, interleukin; PKCd, protein kinase C-d; PMA, phorbol 12- inverse agonists to inhibit histamine signaling by blocking H1R or 43 108 myristate 13-acetate; PUM1, pumilio RNA binding family member 1; Th1/Th2, suppressing H1R signaling (2,3). Therefore, antihistamines are 44 helper T cell type 1/2; TDI, toluene-2,4-diisocyanate. 109 employed as first-line treatment for the nasal symptoms of 45 * Corresponding author. Department of Molecular Pharmacology, Institute of 110 pollinosis. Q2 46 Biomedical Sciences, Tokushima University Graduate School, 1-78-1 Sho-machi, 111 Tokushima 770-8505, Japan. Tel./fax: þ81 88 633 7264. H1R gene expression strongly correlates with the severity of 47 112 E-mail address: [email protected] (H. Mizuguchi). allergic symptoms in toluene-2,4-diisocyanate (TDI)-sensitized rats 48 113 Peer review under responsibility of Japanese Pharmacological Society. and patients with pollinosis (4,5). Further, the suppression of 49 1 Present address: Pharmacy Discipline Khulna University, Khulna, Bangladesh. 114 Q1 upregulated H1R gene expression alleviates nasal symptoms (6e9). 50 2 Present address: Department of Pharmacy Jahangirnagar University, Dhaka, 115 Allergic reactions are characterized further by disrupting the T 51 Bangladesh. 116 3 H.M. and A.K.D. contributed equally to this work. helper cell type 1/2 (Th1/Th2) balance generating a pronounced 52 117 53 http://dx.doi.org/10.1016/j.jphs.2016.02.002 118 54 1347-8613/© 2016 Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society. This is an open access article under the CC BY-NC-ND license 119 (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article in press as: Mizuguchi H, et al., Antihistamines suppress upregulation of histidine decarboxylase gene expression with potencies different from their binding affinities for histamine H1 receptor in toluene 2,4-diisocyanate-sensitized rats, Journal of Pharmacological Sciences (2016), http://dx.doi.org/10.1016/j.jphs.2016.02.002 JPHS202_proof ■ 17 February 2016 ■ 2/7 2 H. Mizuguchi et al. / Journal of Pharmacological Sciences xxx (2016) 1e7 1 Th2 profile (10). Th2 cytokine genes, including interleukin (IL)-4 not take antihistamines or any other treatment were designated as 66 2 and IL-5 genes, are upregulated in TDI-sensitized rats and patients the no treatment group. 67 3 with pollinosis; their expression levels were correlated with that of Total RNA isolated using the RNAqueous Micro Kit (Applied 68 4 H1R gene (4,7,11), suggesting crosstalk between the H1R and Th2 Biosystems, Foster City, CA) was reverse transcribed using the 69 5 cytokine signaling pathways. Intranasal application of IL-4 and High Capacity cDNA Reverse Transcription Kit (Applied Bio- 70 6 histamine increases H1R gene and IL-4 gene expression, respec- systems). The sequences of the HDC primers and TaqMan probe 71 7 tively (7). These findings suggest that H1R signaling is important for are listed in Table 1. The pumilio RNA binding family member 1 72 8 pollinosis development and that drugs designed to suppress H1R (PUM1) primer and probe kit (Hs 00206469-m1, Applied Bio- 73 9 signaling will be effective for treating allergies. systems) was used to generate a standard (5).Thedataare 74 10 Because histidine decarboxylase (HDC) is the only enzyme that expressed as the ratio of HDC mRNA to PUM1 mRNA as previ- 75 11 catalyzes histamine synthesis, HDC gene expression is an impor- ously described. The ethics committee of Tokushima University 76 12 tant regulatory step in histamine signaling (12). Histamine is Hospital and Yashima General Hospital approved this study; 77 13 released from subcutaneous mast cells during the anaphylaxis written informed consent was obtained from each patient before 78 14 phase via an IgE-mediated mechanism, whereas in the post- the study commenced. 79 15 anaphylaxis phase, histamine is produced because of an 80 16 increased HDC activity (13). HDC mRNA levels increase in patients 2.2. Animal studies 81 17 with allergic rhinitis and bronchial asthma (14). Application of TDI 82 18 upregulates HDC mRNA expression and HDC enzymatic activity Six-week-old male Brown Norway rats (200e250 g, Japan SLC, 83 19 and histamine content in the nasal mucosa (7). Moreover, sup- Hamamatsu, Japan) with free access to water were kept in a room 84 20 pression of HDC gene expression alleviates the nasal symptoms of maintained at constant temperature (25 ± 2 C) and humidity 85 21 TDI-sensitized rats. (55% ± 10%) with 12-h light/dark cycle. TDI-sensitization was per- 86 22 Here we show that preseasonal prophylactic treatment with formed as previously reported (12). Antihistamines were orally 87 23 antihistamines suppressed the upregulation of HDC mRNA administered once daily for 3 weeks. The number of sneezes was 88 24 expression in patients with pollinosis and that the expression level measured during the 10-min period just after (early phase reaction) 89 25 of HDC mRNA was strongly correlated with that of H1R mRNA. or 9 h (late phase reaction) after TDI provocation. The antihista- 90 fi 26 Because insuf cient data are available on the effect of antihista- mines (10 mg/kg each) were orally administered 1 h before TDI 91 27 mines on HDC gene expression, we used TDI-sensitized rats to provocation, whereas the control group received water. All exper- 92 28 investigate the effects of antihistamines on nasal symptoms, his- imental procedures were performed in accordance with the 93 29 tamine levels in nasal discharges, HDC activity, and HDC gene guidelines of the Animal Research Committee of Tokushima 94 30 expression in the nasal mucosa. Our data suggest that during the University. 95 31 late-phase response, mepyramine and diphenhydramine signifi- 96 32 cantly suppressed TDI-induced upregulation of HDC mRNA, HDC 97 2.3. Real-time quantitative reverse transcription polymerase chain 33 activity, and histamine content in the nasal mucosa with potencies 98 3 reaction 34 that differed from their Ki values for [ H]mepyramine binding af- 99 35 finity to H1R. 100 Rat nasal mucosa samples collected using RNAlater (Applied 36 101 Biosystems, Foster City, CA, USA) 4 h after provocation were ho- 37 102 mogenized using a Polytron (Model PT-K; Kinematica AG, Littau/ 38 2.
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