RUDN Journal of MedicineRUDN Journal of MedicineВестник Российского университета дружбы народов. Серия: Медицина2313-02452313-0261Peoples’ Friendship University of Russia named after Patrice Lumumba (RUDN University)3610010.22363/2313-0245-2023-27-3-329-341PEYTWLIMMUNOLOGYИММУНОЛОГИЯResearch ArticleInflammatory response modulation by epinephrine and norepinephrineМодуляция воспалительного ответа адреналином и норадреналиномhttps://orcid.org/0000-0001-6186-2462GuryanovaSvetlana V.ГурьяноваС. В.svgur@mail.ruhttps://orcid.org/0009-0001-8107-089XFerbergArtem S.ФербергА. С.svgur@mail.ruhttps://orcid.org/0009-0008-2254-6932SigmatulinIlya A.СигматулинИ. А.svgur@mail.ruM.M. Shemyakin and Yu.A. Ovchinnikov Institute of Bioorganic ChemistryИнститут биоорганической химии им. академиков М.М. Шемякина и Ю.А. Овчинникова Российской академии наукRUDN UniversityРоссийский университет дружбы народовMoscow State UniversityМосковский государственный университет28092023273PHYSIOLOGYФИЗИОЛОГИЯ32934128092023Copyright ©; 2023, Guryanova S.V., Ferberg A.S., Sigmatulin I.A.Copyright ©; 2023, Гурьянова С.В., Ферберг А.С., Сигматулин И.А.2023Guryanova S.V., Ferberg A.S., Sigmatulin I.A.Гурьянова С.В., Ферберг А.С., Сигматулин И.А.https://creativecommons.org/licenses/by-nc/4.0https://journals.rudn.ru/medicine/article/view/36100

Relevance. Inflammation is a defense response of an organism to a pathogen. It appears in order to maintain homeostasis and is regulated by the immune, nervous, and endocrine systems. The hormones epinephrine and norepinephrine are produced in the adrenal medulla and in the brain, and are universal messengers that trigger the transmission of nerve impulses at synapses, and also have a receptor-mediated effect on immunocompetent cells. The aim of this study was to investigate adrenergic pathway regulation of inflammation on the neutrophil granulocytes in the presence of activators of innate immunity receptors. Materials and Methods. Neutrophil granulocytes were obtained from peripheral blood of healthy volunteers in a density gradient of Histopaque 1077 and Histopaque 1119 (Sigma Aldrich, Steinheim, Germany), and cultured in the presence of LPS, GMDP, epinephrine and norepinephrine. The amount of human neutrophil peptides 1-3 (HNP1-3) was examined using an enzyme-linked immunosorbent assay; the gene expression of TLR4, NOD2, ATF3 and A20 was determined using RT-PCR. Results and Discussion. Norepinephrine (noradrenaline) was found to decrease the synthesis of human neutrophils peptides 1-3 (HNP 1-3 defensins, alone and in the combination with agonists of TLR4 and NOD2 receptors - LPS and GMDP respectively. It was found out that there was no a statistically significant effect of epinephrine (adrenaline) on the production of HNP 1-3, including when combined with LPS and GMDP. As a result of the study, an increase in the levels of expression of the genes TLR4, NOD2 and regulator of inflammatory reactions A20 both in LPS- and GMDP- induced neutrophil culture were uncovered, while ATF3 was increased only in LPS-induced neutrophil culture. Epinephrine demonstrated the absence of a statistically significant effect on the expression of the studied genes. While norepinephrine significantly increased the expression of A20 genes. Conclusion. The data obtained shows that norepinephrine can reduce the synthesis of HNP 1-3, including the one induced by LPS and GMDP. Moreover, the ability of norepinephrine to induce the expression of A20 may play a significant role in modulation of inflammation.

Актуальность. Воспаление является защитной реакцией организма на патоген с целью поддержания гомеостаза и регулируется иммунной, нервной и эндокринной системами. Гормоны адреналин и норадреналин вырабатываются в мозговом веществе надпочечников и в головном мозге и являются универсальными мессенджерами, запускающими передачу нервного импульса в синапсах, а также оказывают рецептор-опосредованное действие на иммунокомпетентные клетки. Цель настоящего исследования - изучение адренергического пути регуляции воспаления нейтрофильных гранулоцитов в присутствии активаторов рецепторов врожденного иммунитета. Материалы и методы. Нейтрофильные гранулоциты получали из периферической крови здоровых добровольцев в градиенте плотности Histopaque 1077 и Histopaque 1119 (Sigma Aldrich, Штайнхайм, Германия) и культивировали в присутствии липополисахарида (ЛПС), глюкозаминилмурамилдипептида (ГМДП), адреналина и норадреналина. Количество нейтрофильных пептидов человека 1-3 (HNP1-3) исследовали с помощью иммуноферментного анализа; экспрессию генов TLR4, NOD2, ATF3 и A20 определяли с помощью RT-PCR. Результаты и обсуждение. Установлено, что норадреналин снижает синтез дефензинов HNP 1-3 как отдельно, так и в сочетании с агонистами рецепторов TLR4 и NOD2 - ЛПС и ГМДП соответственно. Установлено отсутствие статистически значимого влияния адреналина на продукцию HNP 1-3, в том числе при сочетании с ЛПС и ГМДП. В результате исследования выявлено повышение уровня экспрессии генов TLR4, NOD2 и регулятора воспалительных реакций А20 как в ЛПС-, так и в ГМДП-индуцированной культуре нейтрофилов, тогда как уровень ATF3 повышался только в ЛПС-индуцированной культуре нейтрофилов. Адреналин продемонстрировал отсутствие статистически значимого влияния на экспрессию исследуемых генов, тогда как норадреналин значительно повышал экспрессию А20. Выводы. Полученные данные показывают, что норадреналин способен снижать синтез HNP 1-3, в том числе индуцируемый ЛПС и ГМДП. Более того, способность норадреналина индуцировать экспрессию А20 может играть значительную роль в модуляции воспаления.

innate immunityTLR4NOD2LPSmuramyl peptidedefensinshuman neutrophil peptides 1-3epinephrinenorepinephrinecatecholamineinflammation regulationврожденный иммунитетTLR4NOD2ЛПСмурамилпептиддефензиныпептиды нейтрофилов человека 1-3адреналиннорадреналинкатехоламинырегуляция воспаленияThis paper has been supported by the RUDN University Strategic Academic Leadership Program.Работа выполнена при поддержке Программы стратегического академического лидерства РУДНLi P, Chang M Roles of PRR-Mediated Signaling Pathways in the Regulation of Oxidative Stress and Inflammatory Diseases. Int. J. Mol. Sci. 2021;19:7688. https://doi.org/10.3390/ijms22147688.Nie L, Cai SY, Shao JZ, Chen J. Toll-Like Receptors, Associated Biological Roles, and Signaling Networks in Non-Mammals. Front. Immunol. 2018;9:1523. https://doi.org/10.3389/fimmu.2018.01523.Guryanova SV, Ovchinnikova TV. Innate Immunity Mechanisms in Marine Multicellular Organisms. Mar. Drugs. 2022;20:549. https://doi.org/10.3390/md20090549.Cai S-Q, Zhang Q, Zhao X-H, Shi J. The In Vitro Anti-Inflammatory Activities of Galangin and Quercetin towards the LPS-Injured Rat Intestinal Epithelial (IEC-6) Cells as Affected by Heat Treatment. Molecules 2021;26:7495. doi: 10.3390/molecules26247495.Šudomová M, Hassan STS. Nutraceutical Curcumin with Promising Protection against Herpesvirus Infections and Their Associated Inflammation: Mechanisms and Pathways. Microorganisms. 2021;9:292. https://doi.org/10.3390/microorganisms9020292.Hwang S-J, Wang J-H, Lee J-S, Kang J-Y, Baek D-C, Kim G-H, Ahn Y-C, Son C-G. Ginseng Sprouts Attenuate Mortality and Systemic Inflammation by Modulating TLR4/NF-κB Signaling in an LPS-Induced Mouse Model of Sepsis. Int. J. Mol. Sci. 2023;24:1583. https://doi.org/10.3390/ijms24021583.Yoon JH, Kim M-Y, Cho JY. Apigenin: A Therapeutic Agent for Treatment of Skin Inflammatory Diseases and Cancer. Int. J. Mol. Sci. 2023;24:1498. https://doi.org/10.3390/ijms24021498.Hoeng J, Boue S, Fields B, Park J, Peitsch MC, Schlage WK, Talikka M, Binenbaum I, Bondarenko V, Bulgakov OV, Cherkasova V, Diaz-Diaz N, Fedorova L, Guryanova S, Guzova J, Igorevna Koroleva G, Kozhemyakina E, Kumar R, Lavid N, Lu Q, Menon S, Ouliel Y, Peterson SC, Prokhorov A, Sanders E, Schrier S, Schwaitzer Neta G, Shvydchenko I, Tallam A, Villa-Fombuena G, Wu J, Yudkevich I, Zelikman M. Enhancement of COPD biological networks using a web-based collaboration interface. F1000Res. 2015;4. doi: 10.12688/f1000research.5984.2.Tataurshchikova NS. ОМ-85: Personalized approach to the treatment of acute respiratory infections in children. Voprosy Prakticheskoi Pediatriithis link is disabled. 2020;15(1):61-68. (in Russian). doi: 10.20953/1817-7646-2020-1-61-68. [Татаурщикова Н.С. ОМ-85: персонифицированный подход в лечении ОРИ у детей. Вопросы практической педиатрии // 2020. Т. 15. № 1. С. 61-68. doi: 10.20953/1817-7646-2020-1-61-68].Guryanova SV. Regulation of Immune Homeostasis via Muramyl Peptides-Low Molecular Weight Bioregulators of Bacterial Origin. Microorganisms. 2022;10(8):1526. https://doi.org/10.3390/microorganisms10081526.Negroni A, Pierdomenico M, Cucchiara S, Stronati L. NOD2 and inflammation: current insights. J. Inflamm. Res. 2018,11:49-60. doi: 10.2147/JIR.S137606.Yao Q, Shen M, McDonald C, Lacbawan F, Moran R, Shen B. NOD2-associated autoinflammatory disease: a large cohort study. Rheumatology. 2015;54(10):1904-1912, https://doi.org/10.1093/rheumatology/kev207.Branquinho D, Freire P, Sofia C. NOD2 mutations and colorectal cancer - Where do we stand? World J Gastrointest Surg. 2016;8(4):284-93. doi: 10.4240/wjgs.v8.i4.284.Dickerson SS, Gable SL, Irwin MR, Aziz N, Kemeny ME. Social-evaluative threat and proinflammatory cytokine regulation: an experimental laboratory investigation. Psychol Sci. 2009;20(10):1237-44. doi: 10.1111/j.1467-9280.2009.02437.x.Miller GE, Rohleder N, Stetler C, Kirschbaum C. Clinical depression and regulation of the inflammatory response during acute stress. Psychosom Med. 2005;67(5):679-87. doi: 10.1097/01.psy.0000174172.82428.ce.Miller SI, Ernst RK, Bader MW. LPS, TLR4 and infectious disease diversity. Nat Rev Microbiol. 2005;3(1):36-46. doi: 10.1038/nrmicro1068.Kirschning CJ, Wesche H, Merrill Ayres T, Rothe M. Human toll-like receptor 2 confers responsiveness to bacterial lipopolysaccharide. J Exp Med. 1998;188(11):2091-7. doi: 10.1084/jem.188.11.2091.Gorshkova RP, Isakov VV, Nazarenko EL, Ovodov YS, Guryanova SV, Dmitriev BA. Structure of the O-specific polysaccharide of the lipopolysaccharide from Yersinia kristensenii O:25.35. Carbohydr Res. 1993;241:201-208. doi: 10.1016/0008-6215(93)80106-o.L’vov VL, Gur’ianova SV, Rodionov AV, Dmitriev BA, Shashkov AS, Ignatenko AV, Gorshkova RP, Ovodov IS. The structure of a repetitive unit of the glycerolphosphate-containing O-specific polysaccharide chain from Yersinia kristensenii strain 103 (0:12,26) lipopolysaccharide. Bioorganicheskaia khimiia. 1990;16(3):379-389.L’vov VL, Gur’yanova SV, Rodionov AV, Gorshkova RP. Structure of the repeating unit of the O-specific polysaccharide of the lipopolysaccharide of Yersinia kristensenii strain 490 (O:12,25). Carbohydr Res. 1992;228(2):415-422. doi:10.1016/0008-6215(92)84134-e.Girardin SE, Travassos LH, Hervé M, Blanot D, Boneca IG, Philpott DJ, Sansonetti PJ, Mengin-Lecreulx D. Peptidoglycan molecular requirements allowing detection by Nod1 and Nod2. J Biol Chem. 2003;278(43):41702-8. doi: 10.1074/jbc.M307198200.Guryanova SV, Khaitov RM. Glucosaminylmuramyldipeptide - GMDP: effect on mucosal immunity (on the issue of immunotherapy and immunoprophylaxis). Immunologiya. 2020;41(2):174-83. (in Russian). doi: 10.33029/0206-4952-2020-41-2-174-183. [Гурьянова С.В., Хаитов РМ. Глюкозаминилмурамилдипептид - ГМДП: воздействие на мукозальный иммунитет (к вопросу иммунотерапии и иммунопрофилактики). Иммунология // 2020. T. 41. № 2. С. 174-183. doi: 10.33029/0206-4952-2020-41-2-174-183].Guryanova S.V., Khaitov R.M. Glucosaminylmuramyl dipeptide in treatment and prevention of infectious diseases. Infectious diseases. News, Opinions, Training, 2020;9(3): 79-86. doi: https://doi.org/10. 33029/2305-3496-2020-9-3-79-86. (In Russian). [Гурьянова С.В., Хаитов Р.М. Глюкозаминилмурамилдипептид в терапии и профилактике инфекционных заболеваний // Инфекционные болезни: новости, мнения, обучение. 2020. Т. 9. № 3. С. 79-86. doi: https://doi.org/10.33029/2305-3496-2020-9-3-79-86].Rechkina EA, Denisova GF, Masalova OV, Lideman LF, Denisov DA, Lesnova EI, Ataullakhanov RI, Gur’ianova SV, Kushch AA. Epitope mapping of antigenic determinants of hepatitis C virus proteins by phage display. Mol Biol (Mosk). 2006;40(2):357-68.Manapova ER, Fazylov VKh, Guryanova SV. Cytopenia and their correction in antiviral therapy of chronic hepatitis C in patients with genotype 1. Problems of Virology. 2017;62(4):174-8. (in Russian). doi: 10.18821/0507-4088-2017-62-4-174-178. [Манапова Э.Р., Фазылов В.Х., Гурьянова С.В. Цитопении и их коррекция при противовирусной терапии хронического гепатита С у пациентов с генотипом 1. Вопросы вирусологии // 2017. Т. 62. № 4. С. 174-8. doi: 10.18821/0507-4088-2017-62-4-174-178].Guryanova SV, Kudryashova NA, Kataeva AA, Orozbekova BT, Kolesnikova NV, Chuchalin AG. Novel approaches to increase resistance to acute respiratory infections. RUDN Journal of Medicine. 2021;25(3):181-195. doi: 10.22363/2313-0245-2021-25-3-181-195.Tank AW, Lee Wong D. Peripheral and central effects of circulating catecholamines. Compr Physiol. 2015;5(1):1-15. doi: 10.1002/cphy.c140007.Marino F, Cosentino M. Adrenergic modulation of immune cells: an update. Amino Acids. 2013;45(1):55-71. doi: 10.1007/s00726-011-1186-6.Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES. The Sympathetic Nerve - An Integrative Interface between Two Supersystems: The Brain and the Immune System. Pharmacol. Rev. 2000;52(4): 595-638Lorton D, Bellinger DL. Molecular mechanisms underlying β-adrenergic receptor-mediated cross-talk between sympathetic neurons and immune cells. Int J Mol Sci. 2015;16(3):5635-65. doi: 10.3390/ijms16035635.Mravec B. Role of catecholamine-induced activation of vagal afferent pathways in regulation of sympathoadrenal system activity: negative feedback loop of stress response. Endocr Regul. 2011;45(1):37-41.Wahle M, Greulich T, Baerwald CG. Influence of catecholamines on cytokine production and expression of adhesion molecules of human neutrophils in vitro. Immunobiol. 2005;21(1):43-52. doi: 10.1016/j.imbio.2005.02.004.Marino F, Scanzano A, Pulze L, Pinoli M, Rasini E, Luini A, Bombelli R, Legnaro M, de Eguileor M, Cosentino M. β2-Adrenoceptors inhibit neutrophil extracellular traps in human polymorphonuclear leukocytes. J Leukoc Biol. 2018;104(3):603-614. doi: 10.1002/JLB.3A1017-398RR.Giraldo E, Hinchado MD, Ortega E. Combined activity of post-exercise concentrations of NA and eHsp72 on human neutrophil function: role of cAMP.J. Cell Physiol. 2013;228(9):1902-1906. https://doi.org/10.1002/jcp.24354.Faurschou M, Borregaard N. Neutrophil granules and secretory vesicles in inflammation. Microbes Infect. 2003;5:1317-1327. https://doi.org/10.1016/j.micinf.2003.09.008.Rice WG, Ganz T, Kinkade JM Jr, Selsted ME, Lehrer RI, Parmley RT. Defensin-rich dense granules of human neutrophils. Blood. 1987;70(3):757-65.Yamamoto-Furusho JK, Barnich N, Hisamatsu T, Podolsky DK. MDP-NOD2 stimulation induces HNP-1 secretion, which contributes to NOD2 antibacterial function. Inflamm Bowel Dis. 2010;16(5):736-42. doi: 10.1002/ibd.21144.Selsted ME, Ouellette AJ. Mammalian defensins in the antimicrobial immune response. Nat Immunol. 2005;6:551-7.Caruso R, Warner N, Inohara N, Núñez G. NOD1 and NOD2: signaling, host defense, and inflammatory disease. Immunity. 2014;41(6):898-908. doi: 10.1016/j.immuni.2014.12.010.De Nardo D. Toll-like receptors: Activation, signalling and transcriptional modulation. Cytokine. 2015;74(2):181-9. doi: 10.1016/j.cyto.2015.02.025.Prescott JA, Mitchell JP, Cook SJ. Inhibitory feedback control of NF-κB signalling in health and disease. Biochem J. 2021;478(13):2619-2664. doi: 10.1042/BCJ20210139.Ku HC, Cheng CF. Master Regulator Activating Transcription Factor 3 (ATF3) in Metabolic Homeostasis and Cancer. Front Endocrinol (Lausanne). 2020;11:556. doi: 10.3389/fendo.2020.00556.Martens A, van Loo G. A20 at the Crossroads of Cell Death, Inflammation, and Autoimmunity. Cold Spring Harb Perspect Biol. 2020;12(1): a036418. doi: 10.1101/cshperspect.a036418.Dömer D, Walther T, Möller S, Behnen M and Laskay T. Neutrophil Extracellular Traps Activate Proinflammatory Functions of Human Neutrophils. Front. Immunol. 2021;12:636954. doi: 10.3389/fimmu.2021.636954.Guryanova, SV, Kataeva, A. Inflammation Regulation by Bacterial Molecular Patterns. Biomedicines 2023;11:183. https://doi.org/10.3390/biomedicines11010183Guryanova SV, Khaitov RM. Strategies for Using Muramyl Peptides - Modulators of Innate Immunity of Bacterial Origin - in Medicine. Front Immunol. 2021;12:607178. doi:10.3389/fimmu.2021.607178Herrero-Cervera A, Soehnlein O, Kenne E. Neutrophils in chronic inflammatory diseases. Cell Mol Immunol. 2022;19(2):177-191. doi: 10.1038/s41423-021-00832-3.Grüneboom A, Aust O, Cibir Z, Weber F, Hermann DM, Gunzer M. Imaging innate immunity. Immunol Rev. 2022;306(1):293-303. doi: 10.1111/imr.13048.Drab E, Sugihara K. Cooperative Function of LL-37 and HNP1 Protects Mammalian Cell Membranes from Lysis. Biophys J. 2020;119(12):2440-2450. doi: 10.1016/j.bpj.2020.10.031.Uriarte SM, Rane MJ, Luerman GC, Barati MT, Ward RA, Nauseef WM, McLeish KR. Granule exocytosis contributes to priming and activation of the human neutrophil respiratory burst. J Immunol. 2011;187(1):391-400. doi: 10.4049/jimmunol.1003112.Zhu CL, Wang Y, Liu Q, Li HR, Yu CM, Li P, Deng XM, Wang JF. Dysregulation of neutrophil death in sepsis. Front Immunol. 2022;13:963955. doi: 10.3389/fimmu.2022.963955.Katkat F, Varol S, Işıksaçan N, Turhan Çağlar FN, Akın F, Karabulut D, Okuyan E. Human neutrophil peptides 1-3 level in patients with acute myocardial infarction and its relation with coronary artery disease severity. Turk Kardiyol Dern Ars. 2021;49(2):120-126. doi: 10.5543/tkda.2021.99537.Cheng FJ, Zhou XJ, Zhao YF, Zhao MH, Zhang H. Human neutrophil peptide 1-3, a component of the neutrophil extracellular trap, as a potential biomarker of lupus nephritis. Int J Rheum Dis. 2015;18(5):533-40. doi: 10.1111/1756-185X.12433.Mothes H, Melle C, Ernst G, Kaufmann R, von Eggeling F, Settmacher U. Human Neutrophil Peptides 1-3-early markers in development of colorectal adenomas and carcinomas. Dis Markers. 2008;25(2):123-9. doi: 10.1155/2008/693937.Xu D, Lu W. Defensins: A Double-Edged Sword in Host Immunity. Front Immunol. 2020;11:764. doi: 10.3389/fimmu.2020.00764.Ihi T, Nakazato M, Mukae H, Matsukura S. Elevated Concentrations of Human Neutrophil Peptides in Plasma, Blood, and Body Fluids from Patients with Infections. Clin. Infect. Dis. 1997;25:1134-1140.Quinn K, Henriques M, Parker T, Slutsky AS, Zhang H. Human neutrophil peptides: a novel potential mediator of inflammatory cardiovascular diseases. Am J Physiol Heart Circ Physiol. 2008;295(5): H1817-24. doi: 10.1152/ajpheart.00472.2008.Miller GE, Rohleder N, Stetler C, Kirschbaum C. Clinical depression and regulation of the inflammatory response during acute stress. Psychosom Med. 2005;67(5):679-87. doi: 10.1097/01.psy.0000174172.82428.ce.Ağaç D, Gill MA, Farrar JD. Adrenergic Signaling at the Interface of Allergic Asthma and Viral Infections. Front Immunol. 2018;9:736. doi: 10.3389/fimmu.2018.00736.Guryanova SV, Gigani OB, Gudima GO, Kataeva AM, Kolesnikova NV. Dual Effect of Low Molecular Weight Bioregulators of Bacterial Origin in Experimental Model of Asthma. Life. 2022;12:192. https://doi.org/10.3390/life12020192.Baliu-Pique M., Jusek G., Holzmann B. Neuroimmunological communication via CGRP promotes the development of a regulatory phenotype in TLR4-stimulated macrophages. European Journal of Immunology. 2014;44(12):3708-3716. doi: 10.1002/eji.201444553.Chang EY, Guo B, Doyle SE, Cheng G. Cutting edge: involvement of the type I IFN production and signaling pathway in lipopolysaccharide-induced IL-10 production. Journal of Immunology. 2007;178(11):6705-6709. doi: 10.4049/jimmunol.178.11.6705.Iyer SS, Ghaffari AA, Cheng G. Lipopolysaccharide-mediated IL-10 transcriptional regulation requires sequential induction of type I IFNs and IL-27 in macrophages. Journal of Immunology. 2010;185(11):6599-6607. doi: 10.4049/jimmunol.1002041.Ernst O, Glucksam-Galnoy Y, Athamna M, Ben-Dror I, Ben-Arosh H, Levy-Rimler G, Fraser IDC, Zor T. The cAMP Pathway Amplifies Early MyD88-Dependent and Type I Interferon-Independent LPS-Induced Interleukin-10 Expression in Mouse Macrophages. Mediators Inflamm. 2019;2019:3451461. doi: 10.1155/2019/3451461.Brightbill HD, Plevy SE, Modlin RL, Smale STA prominent role for Sp1 during lipopolysaccharide-mediated induction of the IL-10 promoter in macrophages. Journal of Immunology. 2000;164(4):1940-1951. doi: 10.4049/jimmunol.164.4.1940.Goldsmith M, Avni D, Ernst O. Synergistic IL-10 induction by LPS and the ceramide-1-phosphate analog PCERA-1 is mediated by the cAMP and p38 MAP kinase pathways. Molecular Immunology. 2009;46(10):1979-1987. doi: 10.1016/j.molimm.2009.03.009.Thompson MR, Xu D, Williams BR. ATF3 transcription factor and its emerging roles in immunity and cancer. J Mol Med (Berl). 2009;87(11):1053-60. doi: 10.1007/s00109-009-0520-x.Shembade N, Harhaj E. Regulation of NF-κB signaling by the A20 deubiquitinase. Cell Mol Immunol. 2012;9:123-130. https://doi.org/10.1038/cmi.2011.59.Chu HM, Tan Y, Kobierski LA, Balsam LB, Comb MJ. Activating transcription factor-3 stimulates 3’,5’-cyclic adenosine monophosphate-dependent gene expression. Mol Endocrinol. 1994;8(1):59-68. doi: 10.1210/mend.8.1.8152431.Kwon JW, Kwon HK, Shin HJ. Activating transcription factor 3 represses inflammatory responses by binding to the p65 subunit of NF-κB. Sci Rep. 2015;5:14470. https://doi.org/10.1038/srep14470.Kolesnikova NV, Kozlov IG, Guryanova SV, Kokov EA, Andronova TM. Clinical and immunological efficiency of muramyl dipeptide in the treatment of atopic diseases. Medical Immunology (Russia). 2016;18(1):15-20. (In Russian). [Колесникова Н.В., Козлов И.Г., Гурьянова С.В., Коков Е.А., Андронова Т.М. Клинико-иммунологическая эффективность и перспективы использования мурамилдипептидов в лечении атопических заболеваний. Медицинская иммунология. 2016. Т. 18. № 1. С. 15-20. doi: 10.15789/1563-0625-2016-1-15-20].Scanzano A, Cosentino M. Adrenergic regulation of innate immunity: a review. Front Pharmacol. 2015;6:171. doi: 10.3389/fphar.2015.00171.