Abstract
Imidazole peptides possess multiple functions, including antioxidant effects, although their biological activities are largely unclear. Their production in humans and animals suggests their physiological roles and validates their safety for pharmaceutical or supplemental use. This study investigated the in vitro anti-anaphylactic potential of two histidine-containing dipeptides, carnosine and anserine in mast cells and basophils. Carnosine and anserine reduced mast cell degranulation elicited by anti-ovalbumin monoclonal IgE and ovalbumin or ionomycin in rat basophilic leukemia RBL2H3 cells without affecting cell viability. In contrast, interleukin-4 production following stimulation was enhanced in the presence of carnosine. Carnosine and anserine strongly inhibited Akt phosphorylation and moderately inhibited ERK phosphorylation. However, these peptides enhanced the increase in phosphorylated JNK levels upon IgE stimulation. The phosphorylation levels of p38 were not affected by carnosine or anserine. To determine the effect of carnosine on basophils, we established a method for detecting IgE-dependent activation in primary cultured mouse splenic basophils via CD63 expression for the first time. Carnosine treatment significantly reduced the increase in CD63 surface expression, a marker of degranulation, in mouse splenic basophils stimulated with anti-IgE. Flow cytometory analysis revealed that mean fluorescence intensities for non-stimulated, anti-IgE-stimulated, and carnosine-pre-treated/anti-IgE-stimulated basophils were 3853 ± 320, 5548 ± 282, and 3853 ± 203, respectively. The findings indicate carnosine and anserine suppress mast cell and basophil IgE-dependent degranulation. The proposed mechanism of the inhibitory effect is the suppression of the activation of phosphoinositide 3-kinase–Akt. Carnosine and anserine may exert anti-anaphylactic effects under physiological and pathological conditions and serve as safe potential drug candidates.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data Availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.
References
Akhalaya MY, Baizhumanov AA, Graevskaya EE (2006) Effects of taurine, carnosine, and casomorphine on functional activity of rat peritoneal mast cells. Bull Exp Biol Med 141:328–330. https://doi.org/10.1007/s10517-006-0162-8
Anderson PC, Dinulos JG (2009) Atopic dermatitis and alternative management strategies. Curr Opin Pediatr 21:131–138. https://doi.org/10.1097/MOP.0b013e32832130a9
Baran J, Sobiepanek A, Mazurkiewicz-Pisarek A, Rogalska M, Gryciuk A, Kuryk L, Abraham SN, Staniszewska M (2023) Mast cells as a target-a comprehensive review of recent therapeutic approaches. Cells 12:1187. https://doi.org/10.3390/cells12081187
Boldyrev AA, Aldini G, Derave W (2013) Physiology and pathophysiology of carnosine. Physiol Rev 93:1803–1845. https://doi.org/10.1152/physrev.00039.2012
Bruhns P, Chollet-Martin S (2021) Mechanisms of human drug-induced anaphylaxis. J Allergy Clin Immunol 147:1133–1142. https://doi.org/10.1016/j.jaci.2021.02.013
Burchett JR, Dailey JM, Kee SA, Pryor DT, Kotha A, Kankaria RA, Straus DB, Ryan JJ (2022) Targeting mast cells in allergic disease: current therapies and drug repurposing. Cells 11:3031. https://doi.org/10.3390/cells11193031
Chez MG, Buchanan CP, Aimonovitch MC, Becker M, Schaefer K, Black C, Komen J (2002) Double-blind, placebo-controlled study of L-carnosine supplementation in children with autistic spectrum disorders. J Child Neurol 17:833–837. https://doi.org/10.1177/08830738020170111501
Ching TT, Hsu AL, Johnson AJ, Chen CS (2001) Phosphoinositide 3-kinase facilitates antigen-stimulated ca(2+) influx in RBL-2H3 mast cells via a phosphatidylinositol 3,4,5-trisphosphate-sensitive ca(2+) entry mechanism. J Biol Chem 276:14814–14820. https://doi.org/10.1074/jbc.M009851200
Duchesne E, Bouchard P, Roussel MP, Côté CH (2013) Mast cells can regulate skeletal muscle cell proliferation by multiple mechanisms. Muscle Nerve 48:403–414. https://doi.org/10.1002/mus.23758
Furuno T, Teshima R, Kitani S, Sawada J, Nakanishi M (1996) Surface expression of CD63 antigen (AD1 antigen) in P815 mastocytoma cells by transfected IgE receptors. Biochem Biophys Res Commun 219:740–744. https://doi.org/10.1006/bbrc.1996.0304
González de Olano D, Cain WV, Bernstein JA, Akin C (2023) Disease spectrum of anaphylaxis disorders. J Allergy Clin Immunol Pract 11:1989–1996. https://doi.org/10.1016/j.jaip.2023.05.012
Hammond C (2023) Revisiting the definition of anaphylaxis. Curr Allergy Asthma Rep 23:249–254. https://doi.org/10.1007/s11882-023-01077-y
Hughes R, Ward D, Tobin AM, Keegan K, Kirby B (2007) The use of alternative medicine in pediatric patients with atopic dermatitis. Pediatr Dermatol 24:118–120. https://doi.org/10.1111/j.1525-1470.2007.00355.x
Hwang B, Song JH, Park SL, Kim JT, Kim WJ, Moon SK (2020) Carnosine impedes PDGF-stimulated proliferation and migration of vascular smooth muscle cells in vitro and sprout outgrowth ex vivo. Nutrients 12:2697. https://doi.org/10.3390/nu12092697
Kim DE, Min KJ, Kim MJ, Kim SH, Kwon TK (2019) Hispidulin inhibits mast cell-mediated allergic inflammation through down-regulation of histamine release and inflammatory cytokines. Molecules 24:2131. https://doi.org/10.3390/molecules24112131
Kozan R, Sefil F, Bağirici F (2008) Anticonvulsant effect of carnosine on penicillin-induced epileptiform activity in rats. Brain Res 1239:249–255. https://doi.org/10.1016/j.brainres.2008.08.019
Liu M, Lu J, Chen Y, Shi X, Li Y, Yang S, Yu J, Guan S (2021) Sodium sulfite-induced mast cell pyroptosis and degranulation. J Agric Food Chem 69:7755–7764. https://doi.org/10.1021/acs.jafc.1c02436
Ma B, Athari SS, Mehrabi Nasab E, Zhao L (2021) PI3K/AKT/mTOR and TLR4/MyD88/NF-κB signaling inhibitors attenuate pathological mechanisms of allergic asthma. Inflammation 44:1895–1907. https://doi.org/10.1007/s10753-021-01466-3
Maspero J, Adir Y, Al-Ahmad M, Celis-Preciado CA, Colodenco FD, Giavina-Bianchi P, Lababidi H, Ledanois O, Mahoub B, Perng DW, Vazquez JC, Yorgancioglu A (2022) Type 2 inflammation in asthma and other airway diseases. ERJ Open Res 8:00576–2021. https://doi.org/10.1183/23120541.00576-2021
Nishida K, Yamasaki S, Hasegawa A, Iwamatsu A, Koseki H, Hirano T (2011) Gab2, via PI-3K, regulates ARF1 in FcεRI-mediated granule translocation and mast cell degranulation. J Immunol 187:932–941. https://doi.org/10.4049/jimmunol.1100360
Oettgen HC (2023) Mast cells in food allergy: inducing immediate reactions and shaping long-term immunity. J Allergy Clin Immunol 151:21–25. https://doi.org/10.1016/j.jaci.2022.10.003
Oppermann H, Faust H, Yamanishi U, Meixensberger J, Gaunitz F (2019) Carnosine inhibits glioblastoma growth independent from PI3K/Akt/mTOR signaling. PLoS ONE 14:e0218972. https://doi.org/10.1371/journal.pone.0218972
Patel RH, Mohiuddin SS (2023) iochemistry, Histamine. May 1. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan–. https://www.ncbi.nlm.nih.gov/books/NBK557790/
Peng W, Mao P, Liu L, Chen K, Zhong Y, Xia W, Guo Q, Tan SC, Rahmani J, Kord Varkaneh H, He P (2020) Effect of carnosine supplementation on lipid profile, fasting blood glucose, HbA1c and insulin resistance: a systematic review and meta-analysis of long-term randomized controlled trials. Complement Ther Med 48:102241. https://doi.org/10.1016/j.ctim.2019.102241
Poto R, Loffredo S, Marone G, Di Salvatore A, de Paulis A, Schroeder JT, Varricchi G (2023) Basophils beyond allergic and parasitic diseases. Front Immunol 14:1190034. https://doi.org/10.3389/fimmu.2023.1190034
Saw S, Arora N (2016) PI3K and ERK1/2 kinase inhibition potentiate protease inhibitor to attenuate allergen induced Th2 immune response in mouse. Eur J Pharmacol 776:176–184. https://doi.org/10.1016/j.ejphar.2016.02.050
Sherman MA (2001) The role of STAT6 in mast cell IL-4 production. Immunol Rev 179:48–56. https://doi.org/10.1034/j.1600-065x.2001.790105.x
Sicklinger F, Meyer IS, Li X, Radtke D, Dicks S, Kornadt MP, Mertens C, Meier JK, Lavine KJ, Zhang Y, Kuhn TC, Terzer T, Patel J, Boerries M, Schramm G, Frey N, Katus HA, Voehringer D, Leuschner F (2021) Basophils balance healing after myocardial infarction via IL-4/IL-13. J Clin Invest 131:e136778. https://doi.org/10.1172/JCI136778
Stevens WW, Kraft M, Eisenbarth SC (2023) Recent insights into the mechanisms of anaphylaxis. Curr Opin Immunol 81:102288. https://doi.org/10.1016/j.coi.2023.102288
Tu H, Li YL (2023) Inflammation balance in skeletal muscle damage and repair. Front Immunol 14:1133355. https://doi.org/10.3389/fimmu.2023.1133355
Varricchi G, Marone G, Kovanen PT (2020) Cardiac mast cells: underappreciated immune cells in cardiovascular homeostasis and disease. Trends Immunol 41:734–746. https://doi.org/10.1016/j.it.2020.06.006
Wallace DV (2023) Knowledge gaps in the diagnosis and management of anaphylaxis. Ann Allergy Asthma Immunol. https://doi.org/10.1016/j.anai.2023.05.010
Yamaki K, Yoshino S (2009) Comparison of inhibitory activities of zinc oxide ultrafine and fine particulates on IgE-induced mast cell activation. Biometals 22:1031–1040. https://doi.org/10.1007/s10534-009-9254-z
Zellweger F, Buschor P, Hobi G, Brigger D, Dahinden CA, Villiger PM, Eggel A (2018) IL-3 but not monomeric IgE regulates FcεRI levels and cell survival in primary human basophils. Cell Death Dis 9:510. https://doi.org/10.1038/s41419-018-0526-9
Acknowledgements
The authors thank Taylor and Francis (https://www.tandfeditingservices.com/) for editing the manuscript.
Author information
Authors and Affiliations
Contributions
Conception and design: KY, YK, KI, HF, KO, MO. Development of methodology: KY, NK, AS. Acquisition of data: KY, NK, N.N, HY, AS, SK. Analysis and interpretation of data: KY, YK, KO, M.O.Writing, review, and/or revision of the manuscript: KY, YK, KI, HF, KO, MO.
Corresponding author
Ethics declarations
Competing interest
KY received research grants from Japan Eco System Co., Ltd.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Yamaki, K., Kamiki, N., Nakatsuka, N. et al. Naturally Occurring Imidazole Peptides, Carnosine and Anserine Inhibit the Degranulation of Mast Cells and Basophils by Modulating Intracellular Signaling. Int J Pept Res Ther 30, 26 (2024). https://doi.org/10.1007/s10989-024-10604-y
Accepted:
Published:
DOI: https://doi.org/10.1007/s10989-024-10604-y