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phorylation of Syk in IgE/Ag-induced BMMCs. In agreement with a previous report (Lee et al., 2008), curcumin was found not to directly inhibit the phosphorylation of Syk, but to inhibit the phosphorylations of LAT and PLCγ1 which lie downstream of Syk. In view of the effect of phosphorylated PLCγ1 on ino- sitol phospholipid turnover and the consequent increase in Ca2+ influx, it is likely that the observed inhibition of Ca2+ influx by curcumin (Fig. 2B) depends on its inhibitory effect on Syk- dependent PLCγ1 phosphorylation. In addition, to our in vitro results, curcumin also suppressed the IgE-dependent PSA reaction in a mast cell-dependent in vivo model of systemic allergic reaction (Wershil et al., 1987) with a potency equiva- lent to that of the H1 histamine antagonist, Fexo (Fig. 1A-C). We already reported that PGD and LTC play important roles bilisation in polymorphonuclear leukocytes involving Src family ki- nases. Biochim. Biophys. Acta 1736, 109-119. Gijon, M. 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(2002) Anaphylaxis: a review of causes and mechanisms. J. Allergy Clin .Immunol. 110, 341-348. Kiuchi, F., Goto, Y., Sugimoto, N., Akao, N., Kondo, K. and Tsuda, Y. (1993) Nematocidal activity of turmeric: synergistic action of cur- cuminoids. Chem. Pharm. Bull. 41, 1640-1643. Kudo, I. and Murakami, M. (1999) Diverse functional coupling of pros- tanoid biosynthetic enzymes in various cell types. Adv. Exp. Med. Biol. 469, 29-35. Lee, J. H., Kim, J. W., Ko, N. Y., Mun, S. H., Her, E., Kim, B. K., Han, J. W., Lee, H. Y, Beaven, M. A., Kim, Y. M. and Choi, W. S. (2008) Curcumin, a constituent of curry, suppresses IgE-mediated allergic response and mast cell activation at the level of Syk. J. Allergy Clin. Immunol. 121, 1225-1231. Lee, K. W., Kim, J. H, Lee, H. J and Surh, Y. J. (2005) Curcumin inhib- its phorbol ester-induced up-regulation of cyclooxygenase-2 and matrix metalloproteinase-9 by blocking ERK1/2 phosphorylation and NF-kappaB transcriptional activity in MCF10A human breast epithelial cells. Antioxid. Redox. Signal. 7, 1612-1620. Lin, L. L., Wartmann, M., Lin, A. Y., Knopf, J. L., Seth, A. and Davis, R. J. (1993) cPLA2 is phosphorylated and activated by MAP kinase. Cell 72, 269-278. Lu, Y., Suh, S. J., Li, X., Hwang, S. L., Li, Y., Hwangbo, K., Park, S. J., Murakami, M., Lee, S. H., Jahng, Y., Son, J. K., Kim, C. H. and Chang, H. W. (2012) Citreorosein, a naturally occurring anthraqui- none derivative isolated from Polygoni cuspidati radix, attenuates cyclooxygenase-2-dependent prostaglandin D2 generation by blocking Akt and JNK pathways in mouse bone marrow-derived mast cells. Food Chem. Toxicol. 50, 913-919. Lu, Y., Yang, J. H., Li, X., Hwangbo, K., Hwang, S. L., Taketomi, Y., Murakami, M., Chang, Y. C., Kim, C. H., Son, J. K and Chang, H. W. (2011) Emodin, a naturally occurring anthraquinone derivative, suppresses IgE-mediated anaphylactic reaction and mast cell acti- vation. Biochem. Pharmacol. 82, 1700-1708. Mazuc, E., Villoutreix, B. O., Malbec, O., Roumier, T., Fleury, S., Le- onetti, J. P., Dombrowicz, D., Daëron, M., Martineau, P. and Dari- avach, P. (2008) A novel druglike spleen tyrosine kinase binder prevents anaphylactic shock when administered orally. J Allergy Clin. Immunol. 122, 188-194. Mehrabian, M. and Allayee, H. (2003) 5-lipoxygenase and atheroscle- rosis. Curr. Opin Lipidol. 14, 447-457. Moon, T. C., Murakami, M., Ashraf, M. D., Kudo, I. and Chang H. W. (1998) Regulation of cyclooxygenase-2 and endogenous cytokine expression by bacterial lipopolysaccharide that acts in synergy with c-kit ligand and Fc epsilon receptor I crosslinking in cultured mast cells. Cell. Immunol. 185, 146-152. Murphy, R. C. and Gijon, M. A. (2007) Biosynthesis and metabolism of leukotrienes. Biochem. J. 405, 379-395 Ram, A., Das, M. and Ghosh, B. (2003) Curcumin attenuates allergen- induced airway hyperresponsiveness in sensitized guinea pigs. Biol. Pharm. Bull. 26, 1021-1024. Reddy, S. T., Wadleigh, D. J. and Herschman, H. R. (2000) Transcrip- tional regulation of the cyclooxygenase-2 gene in activated mast cells. J. Biol. Chem. 275, 3107-3113. 24 in mast cell-mediated anaphylactic reaction (Lu et al., 2011; Hwang et al., 2013). Recently, several reports have demon- strated that Syk kinase inhibitors promised for the treatment of allergic and antibody-mediated autoimmune diseases (Ruzza et al., 2009) and clinical implications of Syk inhibitor showed antiallergic properties when administered orally (Mazuc et al., 2008).Taken together with previous results (Lee et al., 2008), the anti-allergic inflammatory activity of curcumin appear to be due to the suppressions of the secretions of TNF-α and IL-4 and histamine release and eicosanoid generation through the inhibition of Syk kinase pathway in IgE/Ag-induced mast cells. ACKNOWLEDGMENTS This work was supported by Yeungnam University 2013 grant. REFERENCES Ammon, H. P. and Wahl, M. A. (1991) Pharmacology of Curcuma lon- ga. Planta Med. 57, 1-7. Ashraf, M., Murakami, M. and Kudo I. (1996) Cross-linking of the high- affinity IgE receptor induces the expression of cyclo-oxygenase 2 and attendant prostaglandin generation requiring interleukin 10 and interleukin 1 beta in mouse cultured mast cells. Biochem. J. 320, 965-973. Avis, I., Hong, S. H., Martinez, A., Moody, T., Choi, Y. H., Trepel, J., Das, R., Jett, M. and Mulshine, J. L. (2001) Five-lipoxygenase in- hibitors can mediate apoptosis in human breast cancer cell lines through complex eicosanoid interactions. FASEB J. 15, 2007-2009. Cho, J. W., Lee, K. S. and Kim, C. W. (2007) Curcumin attenuates the expression of IL-1β, IL-6, and TNF-α as well as cyclin E in TNF- α-treated HaCaT cells; NF-κB and MAPKs as potential upstream targets. Int. J. Mol. Med. 19, 469-474. Choi, Y. H., Yan, G. H., Chai, O. H. and Song, C. H. (2010) Inhibitory effects of curcumin on passive cutaneous anaphylactoid response and compound 48/80-induced mast cell activation. Anat. Cell Biol. 43, 36-43. Chun, K. S., Keum, Y. S., Han, S. S., Song, Y. S., Kim, S. H. and Surh, Y. J. (2003) Curcumin inhibits phorbol ester-induced expression of cyclooxygenase-2 in mouse skin through suppression of extracel- lular signal regulated kinase activity and NF-κB activation. Carcino- genesis 24, 1515-1524. Ciprandi, G., Tosca, M. A., Cosentino, C., Riccio, A. M., Passalacqua, G. and Canonica, G. W. (2003) Effects of fexofenadine and other antihistamines on components of the allergic response: adhesion molecules. J. Allergy Clin. Immunol. 112, S78-82. Fischer, L., Poeckel, D., Buerker,t E., Steinhilber, D. A D Werz, O. (2005) Inhibitors of actin polymerization stimulate arachidonic acid release and 5-lipoxygenase activation by upregulation of Ca2+ mo- 33 www.biomolther.org Li et al. Curcumin Inhibits Mast Cells Activation and AnaphylaxisPDF Image | Curcumin Inhibits the Activation of Immunoglobulin
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