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Inhibitory Activity of Pranlukast and Montelukas Against Histamine

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Inhibitory Activity of Pranlukast and Montelukas Against Histamine Showa Univ J Med Sci 21（2）, 77～84, June 2009 Original Inhibitory Activity of Pranlukast and Montelukas Against Histamine Release and LTC4 Production from Human Basophils 1, 2 1 1 Satoshi HIBINO ）, Ryoko ITO ）, Taeru KITABAYASHI ）, 1 2 Kazuo ITAHASHI ） and Toshio NAKADATE ） Abstract : Leukotriene receptor antagonists（LTRAs）are routinely used to treat bronchial asthma and are thought to act mostly by inhibiting leukotriene receptors. However, there is no preclinical or clinical evidence of the direct effect of LTRAs on histamine release from and leukotriene（LT）C4 produc- tion by basophils. We used anti-IgE antibody（Ab）, FMLP, and C5a to induce histamine release, and anti-IgE Ab and FMLP to stimulate LTC 4 production. Basophils were exposed to different concentrations of pranlukast and montelu- kast, and then to anti-IgE Ab, FMLP, and C5a. Culture supernatant histamine and LTC 4 levels were measured by using a histamine ELISA kit and a LTC 4 EIA kit, respectively. Histamine release was expressed as a percentage of the total histamine content（％HR）induced by anti-IgE Ab, FMLP, or C5a. To evaluate the effects of pranlukast and montelukast on histamine release and LTC 4 production, we calculated the percent inhibition of histamine release and LTC 4 production, expressed as percent inhibition, at different concentrations of pranlukast and montelukast. Pranlukast significantly inhibited histamine release stimulated by FMLP and C5a, but had no effect on histamine release stimulated by anti-IgE Ab. By comparison, montelukast signicantly inhibited histamine release stimulated by FMLP, C5a, and anti-IgE Ab, in a concentration-dependent manner. Both pranlukast and montelukast signicantly inhibited LTC 4 production stimulated by anti-IgE Ab and FMLP. Together, these ndings demonstrate that LTRAs have a direct inhibitory effect against histamine release and LTC 4 production from basophils and provide new insight into the potential clinical application of LTRAs for the treatment of allergic disease. Key words : basophil, leukotriene, leukotriene receptor antagonist, histamine Introduction Basophils play an important role in the late phase of allergic response by releasing proinflammatory mediators including histamine, cysteinyl leukotrienes（cysLTs）, and pros- 1）Department of Pediatrics, Showa University School of Medicine, 1‒5‒8, Hatanodai, Shinagawa-ku, Tokyo 142‒8666, Japan. 2）Department of Hygieiology, Showa University School of Medicine. 78 Satoshi HIBINO, et al taglandins 1, 2）. Leukotriene receptor antagonists（LTRA）inducing pranlukast, montelukast, and zafirlukast are effective in the treatment of bronchial asthma because they improve forced expiratory volume in one second as well as night-time asthma symptom scores and other clinical parameters in asthmatic patients 3‒6）. LTRAs are thought to exert their pharmacological activity by inhibiting the leukotriene receptors（LTRs）. However, previous studies have suggested that LTRAs interact not only with the cysLT receptors（cysLTRs） but also with allergic inammatory cells in the absence of cysLTR mediation. Tohda et al（1999）demonstrated that pranlukast suppresses the production of interleukin（IL）-4, IL-5, and granulocyte macrophage colony-stimulating factor（GM-CSF）by peripheral blood mononuclear cells in vitro 7）. Furthermore, Ramires et al（2004）revealed that montelukast exerts inhibitory activity against 5-lipoxygenase activity in human mast cells（HMC-1 cells） and human polymorphonuclear leukocytes in vitro 8）. With respect to the inhibitory activity of LTRAs on basophils, Kobi et al（2005）have provided only indirect evidence that mon- telukast, taken orally, inhibits cysLT release from basophils in patients with bronchial asthma after 4 weeks of treatment 9）. The objective of the present in vitro study was to examine the direct effects of pranlukast and montelukast on histamine release and LTC 4 production from human peripheral blood basophils. Materials and Methods We purchased rabbit anti-IgE antibody（Ab）（Dako, Glostrup, Denmark）, N-formyl- methionyl-leucyl-phenylalanine（FMLP）, human recombinant-C5a（C5a）, Histopaque 1.083, C6H18N2O6S2・1.5 Na piperazine diethanesulfonic acid（PIPES）, human serum albumin（HSA）, glucose, perchloric acid（PCA）, and alcian blue（C56H68Cl4CuN16S4）（Sigma, St. Louis, MO）, saline（Otsuka, Naruto, Japan）, ethyl-enediaminetetraacetic acid（EDTA）, NaCl, KCl, MgCl2, CaCl2（Wako, Osaka, Japan）. Pranlukast and montelukast were supplied by Ono Pharmaceutical Co, Ltd. and Banyu Pharmaceutical Co, Ltd., respectively. PIPES-albumin- glucose（PAG）buffer consisted of 25 mM PIPES, 110 mM NaCl, 5 mM KCl, 0.1％ glucose, and 0.003％ HSA. PAGCM consisted of PAG supplemented with 1 mM CaCl2 and 1 mM MgCl2. PAG-EDTA consisted of PAG supplemented with 4 mM EDTA. Purication of basophils According to previously described methods 10, 11）, basophils were puried from peripheral blood taken from healthy volunteer donors（n＝10）who had given consent to enrolment in the present study. Saline at the same volume as the collected peripheral blood and 0.1 M EDTA-2 Na at one-tenth the volume of the blood were mixed with the blood and the mixture was then gently added to Histopaque 1.803. The mixture was centrifuged（300 g, 20 min）to isolate the layer of mononuclear cells including basophils. Mononuclear cells were suspended in PAGCM at a concentration of 5×105 basophils / mL. Basophils were counted Inhibitory activity of LTRAs on basophils 79 following alcian blue staining 12）. Stimulation of basophils Anti-IgE Ab, FMLP, and C5a were used to induce histamine release, whereas and anti- IgE Ab and FMLP were used to induce LTC4 production. Basophils were incubated at 37℃ for 15 minutes with different concentrations（1, 10, and 100 μM）of pranlukast and montelukast, followed by incubation with anti-IgE Ab（1 μg / mL）, FMLP（1 μM）, or C5a （300 ng / mL）at 37° C for 30 minutes. The concentration of used in this study was based on published data 10）, whereas the concentrations of anti-IgE Ab and C5a used in this study were based on determination of the optimal concentrations to induce histamine release. Histamine and LTC4 measurements Reactions were terminated with ice-cold PAG-EDTA and the cells were pelleted by centrifugation at 4500 g for 30 s. Culture supernatant histamine levels were measured with a histamine ELISA kit（Immunotech, Marseille, France）, and culture supernatant LTC4 levels were measured with an LTC4 EIA kit（Cayman Chemical Co, Ann Arbor, AI）. Each mea- surement was performed in duplicate. Percentage of histamine release（％HR）induced with anti-IgE Ab, FMLP, snd C5a was calculated according to the following equation : ％HR＝ （C-C spon）/（C total -C spon）×100（％）, where C is the culture supernatant histamine level in each stimulated blood sample, C spon is the culture supernatant histamine level in the control sample that shows spontaneous histamine release, and C total is the total amount of histamine in basophils that is identied by using PCA to destroy cell membranes. To evaluate the direct effects of pranlukast and montelukast on histamine release, we estimated the percent inhibition of histamine release and LTC4 production at different concentrations of pranlukast and montelukast. Blood samples collected from nonresponders, whose ％HR were not more than 20％ or whose LTC4 production were not more than that of control samples were not used in the statistical analysis. Statistical analysis Values are expressed as mean±SEM. Statistical analyses were performed by the paired Student’s t-test, and a value of P＜0.05 was considered to be statistically signicant. Results Effects of pranlukast and montelukast on histamine release following stimulation by anti-IgE Ab, FMLP, or C5a The mean values（mean±SEM）of ％HR induced by anti-IgE Ab, FMLP, and C5a were 42±4.6％, 44±7.1％, and 25±1.6％, respectively（Table 1）. The effects of pranlukast on histamine release from basophils are shown in Fig. 1A. Pranlukast inhibited FMLP-induced histamine release in a concentration-dependent manner ; this effect was signicant at 10 μM 80 Satoshi HIBINO, et al Table 1 Histamine release from peripheral blood basophils Histamine release（％） Inducer n Mean±SEM Anti-IgE Ab 4 42±4.6 FMLP 5 44±7.1 C5a 5 25±1.6 IgE, immunoglobulin E ; Ab, antibody ; FMLP, N-formyl- methionyl-leucyl-phenylalanine ; C5a, human recombinant C5a ; SEM, standard error of the mean and 100 μM pranlukast with percent inhibition（mean±SEM）values of 55％±10％（P＜0.01） and 87％±5.1％（P＜0.001）, respectively. Pranlukast also signicantly inhibited C5a-induced histamine release with percent inhibition（mean±SEM）values of 80％±6.8％ at 100 μM （P＜0.01）. By comparsion, pranlukast did not inhibit anti-IgE-induced histamine release. The effects of montelukast on histamine release from human basophils are shown in Fig. 1B. Montelukast signicantly inhibited anti-IgE Ab-, C5a-, and FMLP-induced histamine release in a concentration-dependent manner. The percent inhibition of FMLP-induced histamine release by montelukast was 28％±9.4％ at 1 μM（P＜0.05）, 83％±8.8％ at 10 μM（P＜ 0.001）, and 88％±2.9％ at 100 μM（P＜0.001）. The percent inhibition of C5a-induced histamine release by montelukast was 78％±9.4％ at 10 μM（P＜0.01）and 79％±4.8％ at 100 μM（P＜0.001）. The percent inhibition of anti-IgE Ab-induced histamine release by montelukast was 71％±14％ at 10 μM（P＜0.05）and 81％±2.7％ at 100 μM（P＜0.001）. Effects of pranlukast and montelukast on LTC4 production following stimulation by anti-IgE Ab or FMLP. The mean amounts of LTC4 production（mean±SEM）induced by anti-IgE Ab and FMLP were 296±90.7 and 116±28.7（ng / 10 5 basophils）, respectively（Table 2）. The effects of pranlukast on LTC4 production by human basophils are shown in Fig. 2A. Pranlukast inhibited anti-IgE Ab-stimulated LTC4 production ; this effect was signicant at 10 μM with percent inhibition calculated as 50％±31％（P＜0.01）.
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