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)4085610.22363/2313-0245-2024-28-3-365-376DJROANIMMUNOLOGYИММУНОЛОГИЯResearch ArticleInfluence of muramyl peptides on the production of chemokines, growth factors, pro-inflammatory and anti-inflammatory cytokinesВлияние мурамилпептидов на продукцию хемокинов, факторов роста, провоспалительных и противовоспалительных цитокиновhttps://orcid.org/0000-0001-6186-24626722-8695GuryanovaSvetlana V.ГурьяноваС. В.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 народов15092024283PHYSIOLOGY. EXPERIMENTAL PHYSIOLOGYФИЗИОЛОГИЯ. ЭКСПЕРИМЕНТАЛЬНАЯ ФИЗИОЛОГИЯ36537630092024Copyright ©; 2024, Guryanova S.V.Copyright ©; 2024, Гурьянова С.В.2024Guryanova S.V.Гурьянова С.В.https://creativecommons.org/licenses/by-nc/4.0https://journals.rudn.ru/medicine/article/view/40856

Relevance. The recent increase in inflammatory, allergic and infectious diseases needs to update new ways of raising non-specific resistance of the organism. Innate immunity provides the first line of defense against pathogens through the activation of receptors that detect microorganisms: TLRs, NLRs and CLRs. Muramyl peptides that form the cell wall of all known bacteria are recognized by NLRs and trigger immune responses to eliminate pathogens. The aim of this study was to investigate the effect of muramyl peptides on the production of chemokines, growth factors, pro-inflammatory and anti-inflammatory cytokines by human mononuclear cells. Materials and Methods. Mononuclear cells were isolated from the peripheral blood of healthy volunteers using the Cell Separation Media Lympholyte CL 5015 reagent and cultured for 4 hours in the presence of glucosaminyl muramyl dipeptides GMDP, GMDP-OH, GMDP-Lys, GMDP-LL; an adequate amount of medium was added to the control wells. The levels of chemokines, growth factors, proinflammatory and anti-inflammatory cytokines were measured using magnetic beads with antibodies according to the manufacturer’s instructions Luminex 200, Merck (Millipore) equipment, and software (Burlington, Massachusetts, USA). Results and Discussion. It was found that muramyl peptides GMDP, GMDP-ON and GMDP-Lys enhance the production of cytokines IL-1a, IL-1b, IL-1RA, IL-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12P40, IL-12P70, IL-15, MDC, sCD40L, IFNα2, IFN-γ, TNF-a, TNF-β, GM-CSF. GMDP-LL does not affect the production of cytokines. At the same time, muramyl peptides with the L-configuration of alanine and the D-configuration of isoglutamine (L-D muramyl peptides) did not change the values of IL-2, IL-3, IL-5, IL-9. Conclusion. The D-configuration of isoglutamine is fundamental for the implementation of the regulatory activity of muramyl peptides. A wide range of bacterial bioregulators, the source of which are microorganisms, regulate the host homeostasis and trigger immune reactions, which, depending on the context, can have opposite effects. L-D muramyl peptides activate mononuclear cells, which begin to produce proinflammatory cytokines and chemokines, as well as growth factors necessary for the destruction of pathogens. In addition, anti-inflammatory cytokines are also triggered, which have a regulatory role in the appearance of memory cells and the weakening of inflammatory reactions. Thus, normally, muramyl peptides participate in maintaining tolerance to microflora and maintaining immune homeostasis.

Актуальность. Рост воспалительных, аллергических и инфекционных заболеваний, наблюдающийся в последнее время, актуализирует задачу поиска новых способов повышения неспецифической резистентности организма. Врожденный иммунитет обеспечивают первую линию защиты от патогенов через активацию рецепторов, определяющих микроорганизмы посредством рецепторов TLRs, NLRs и CLRs. Мурамилпептиды, образующие клеточную стенку всех известных бактерий, распознаются NLRs и запускают реакции иммунной системы по элиминации патогенов. Целью настоящего исследования являлось изучение влияния мурамилпептидов на продукцию хемокинов, факторов роста, провоспалительных и противовоспалительных цитокинов мононуклеарными клетками. Материалы и методы. Мононуклеарные клетки получали из периферической крови здоровых добровольцев с помощью реагента Cell Separation Media Lympholyte CL 5015 и культивировали 4 часа в присутствии глюкозаминил мурамил дипептидов ГМДП, ГМДП-ОН, ГМДП-Lys, ГМДП-LL; в контрольные лунки добавляли адекватное количество среды. Уровни хемокинов, факторов роста, провоспалительных и противовоспалительных цитокинов измеряли с помощью магнитных шариков с антителами согласно инструкции производителя Luminex 200, Merck (Millipore) equipment, and software (Burlington, Massachusetts, USA). Результаты и обсуждение. Установлено, что мурамилпептиды GMDP, GMDP-ON, GMDP-Lys и усиливают продукцию цитокинов IL-1a, IL-1b, IL-1RA, IL-4, IL-6, IL-10, IL-12P40, IL-12P70, IL-15, MDC, sCD40L, IFNα2, IFN-γ, TNF-a, TNF-β, GM-CSF. GMDP-LL не влияет на продукцию цитокинов. В то же время мурамилпептиды с L-конфигурацией аланина и D-конфигурацией изоглутамина (L-D-мурамилпептиды) не изменили значения IL-2, IL-3, IL-5, IL-9. Выводы. D-конфигурация изоглутамина является необходимой для реализации регуляторной активности мурамилпептидов. Широкий спектр бактериальных биорегуляторов, источником которых являются микроорганизмы, регулируют гомеостаз хозяина и запускают иммунные реакции, которые в зависимости от контекста могут иметь противоположные эффекты. L-D-мурамилпептиды активируют мононуклеарные клетки, которые начинают продуцировать провоспалительные цитокины и хемокины, а также факторы роста, необходимые для уничтожения патогенов. Кроме того, запускаются и противовоспалительные цитокины и хемокины, которые играют регуляторную роль в появлении клеток памяти и ослаблении воспалительных реакций. Таким образом, в норме мурамилпептиды участвуют в поддержании толерантности к микрофлоре и поддержании иммунного гомеостаза.

innate immunityimmune homeostasistoleranceglucosaminylmuramyldipeptidemuramyl peptideinflammation regulationbacterial bioregulatorsNOD2NOD2врожденный иммунитетиммунный гомеостазтолерантностьглюкозаминилмурамилдипептидмурамилпептидрегуляция воспалениябактериальные биорегуляторыJohannsen L. Biological properties of bacterial peptidoglycan. APMIS. 1993;101(5):337-44. doi: 10.1111/j.1699-0463.1993.tb00119.xRohde M. The Gram-­Positive Bacterial Cell Wall. Microbiol Spectr. 2019;7:10.1128/microbiolspec.gpp3-0044-2018. https://doi.org/10.1128/microbiolspec.gpp3-0044-2018Adam A, Petit JF, Lefrancier P, Lederer E. Muramyl peptides. Chemical structure, biological activity and mechanism of action. Mol Cell Biochem. 1981;41:27-47. doi: 10.1007/BF00225295Williams K. Endotoxin definition and standardization. Formulation European Pharmaceutical Review.2019;2:1-9.Raetz CR, Whitfield C. Lipopolysaccharide endotoxins. Annu. Rev. Biochem. 2002;71:635-700.Matsuura M. Structural modifications of bacterial lipopolysaccharide that facilitate Gram-negative bacteria evasion of host innate immunity. Front. Immunol. 2013;4:109. doi: 10.3389/fimmu.2013.00109L’vov VL, Gur’yanova SV, Rodionov A.V., Gorshkova R.P. Structure of the repeating unit of the O-specific polysaccharide of the lipopolysaccharide of Yersinia Kristensenii strain 490 (O:12,25). Carbohydrate Research. 1992;228(2):415-422.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. Carbohydrate Research. 1993;241:201-208. doi: 10.1016/0008-6215(93)80106-oL’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.Lithgow T, Stubenrauch CJ, Stumpf, MPH. Surveying membrane landscapes: a new look at the bacterial cell surface. Nat Rev Microbiol. 2023;21:502-518. https://doi.org/10.1038/s41579-023-00862-wSmith TJ, Blackman SA, Foster SJ. Autolysins of Bacillus subtilis: multiple enzymes with multiple functions. Microbiology. 2000;146:249-262. https://doi.org/10.1099/00221287-146-2-249Johnson JW, Fisher JF, Mobashery S. Bacterial cell-wall recycling. Ann N Y Acad Sci. 2013;1277:54-75 https://doi.org/10.1111/j.1749-6632.2012.06813.xPark JT, Uehara T. How bacteria consume their own exoskeletons (turnover and recycling of cell wall peptidoglycan). Microbiol Mol Biol Rev. 2008;72:211-227 https://doi.org/10.1128/MMBR.00027-07Mitchell JA, Paul-­Clark MJ, Clarke GW, McMaster SK, Cartwright N. Critical role of toll-like receptors and nucleotide oligomerisation domain in the regulation of health and disease. J Endocrinol. 2007;193(3):323-30. doi: 10.1677/JOE-07-0067Jaén RI, Val-­Blasco A, Prieto P, Gil-­Fernández M, Smani T, López-­Sendón JL, Delgado C, Boscá L, Fernández-­Velasco M. Innate Immune Receptors, Key Actors in Cardiovascular Diseases. JACC Basic Transl Sci. 2020;5(7):735-749. doi: 10.1016/j.jacbts.2020.03.015Cui J, Chen Y, Wang HY, Wang RF. Mechanisms and pathways of innate immune activation and regulation in health and cancer. Hum Vaccin Immunother. 2014;10(11):3270-85. doi: 10.4161/21645515.2014.979640Inohara N, Nuñez G. NODs: intracellular proteins involved in inflammation and apoptosis. Nat Rev Immunol. 2003;3(5):371-82. doi: 10.1038/nri1086Kobayashi KS, Chamaillard M, Ogura Y, Henegariu O, Inohara N, Nuñez G, Flavell RA. Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science. 2005;307(5710):731-4. doi: 10.1126/scienceHugot JP, Chamaillard M, Zouali H, Lesage S, Cézard JP, Belaiche J, Almer S, Tysk C, O’Morain CA, Gassull M, Binder V, Finkel Y, Cortot A, Modigliani R, Laurent-­Puig P, Gower-­Rousseau C, Macry J, Colombel JF, Sahbatou M, Thomas G. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature. 2001;31;411(6837):599-603. doi: 10.1038/35079107Hampe J, Cuthbert A, Croucher PJ, Mirza MM, Mascheretti S, Fisher S, Frenzel H, King K, Hasselmeyer A, MacPherson AJ, Bridger S, van Deventer S, Forbes A, Nikolaus S, Lennard-­Jones JE, Foelsch UR, Krawczak M, Lewis C, Schreiber S, Mathew CG. Association between insertion mutation in NOD2 gene and Crohn’s disease in German and British populations. Lancet. 2001;357(9272):1925-8. doi: 10.1016/S0140-6736(00)05063-7Bruns T, Peter J, Hagel S, Pfeifer R, Prinz P, Stallmach A. Homozygous carrier of the NOD2 1007fs frame-­shift mutation presenting with refractory community-­acquired spontaneous bacterial peritonitis and developing fatal pulmonary mucormycosis: A case report. Hepatol Res. 2011;41(10):1009-14. doi: 10.1111/j.1872-034X.2011.00850.xWiest R, Lawson M, Geuking M. Pathological bacterial translocation in liver cirrhosis. J Hepatol. 2014;60(1):197-209. doi: 10.1016/j.jhep.2013.07.044Appenrodt B, Grünhage F, Gentemann MG, Thyssen L, Sauerbruch T, Lammert F. Nucleotide-­binding oligomerization domain containing 2 (NOD2) variants are genetic risk factors for death and spontaneous bacterial peritonitis in liver cirrhosis. Hepatology. 2010;51(4):1327-33. doi: 10.1002/hep.23440Gurunathan S, Thangaraj P, Kim JH. Postbiotics: Functional Food Materials and Therapeutic Agents for Cancer, Diabetes, and Inflammatory Diseases. Foods. 2023;13(1):89. doi: 10.3390/foods13010089Sizyakina LP, Andreeva II, Petruchik SV. Optimization of Therapy of Patient with Genetic Defect Antibody Production. RUDN Journal of Medicine. 2019;23(4):405-411. [Сизякина Л.П., Андреева И.И., Петручик С.В. Оптимизация терапии пациента с генетическим дефектом антителопродукции // Вестник Российского университета дружбы народов. Серия: Медицина. 2019. Т. 23. No 4. С. 405-411]. doi: 10.22363/2313-0245-2019-23-4-405-411Guryanova 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: 10.22363/2313-0245-2021-25-3-181-195Sizyakina LP, Zakurskaya VYa, Guryanova SV. Gluco­saminylmuramyl dipeptide efficacy in post-­COVID-19 patient rehabilitation treatment. Infectious Diseases: News, Opinions, Training. 2023;12 (1):17-25. (in Russian) [Сизякина Л.П., Закурская В.Я., Гурьянова С.В. Эффективность глюкозаминилмурамилдипептида в реабилитации пациентов, перенесших COVID-19 // Инфекционные болезни: новости, мнения, обучение. 2023. Т. 12, № 1. С. 17-25]. doi: https://doi.org/10.33029/2305-3496-2023-12-1-17-25Ellouz F, Adam A, Ciorbaru R, Lederer E. Minimal structural requirements for adjuvant activity of bacterial peptidoglycan derivatives. Biochem Biophys Res Commun. 1974;59(4):1317-25. doi: 10.1016/0006-291x(74)90458-6Chedid L, Parant M, Parant F, Lefrancher P, Choay J, Lederer E. Enhancement of nonspecific immunity to Klebsiella pneumoniae infection by a synthetic immunoadjuvant (N-acetylmuramyl-­L-alanyl-­D-isoglutamine) and several analogs. Proc Natl Acad Sci USA. 1977;74(5):2089-93. doi: 10.1073/pnas.74.5.2089Khan FA, Khanam R, Qasim MW, Wang Y, Jiang ZH. Improved Synthesis of D-Isoglutamine: Rapid Access to Desmuramyl Analogues of Muramyl Dipeptide for the Activation of Intracellular NOD2 Receptor and Vaccine Adjuvant Applications. Eur JOC. 2021;48:6688-6699. https://doi.org/10.1002/ejoc.202101170Johnson AG. Molecular adjuvants and immunomodulators: new approaches to immunization. Clin Microbiol Rev. 1994;7(3):277-89. doi: 10.1128/CMR.7.3.277Kamboj A, Patil MT, Petrovsky N, Salunke DB. Structure-­activity relationship in NOD2 agonistic muramyl dipeptides. Eur J Med Chem. 2024;271:116439. doi: 10.1016/j.ejmech.2024.116439Britanova OV, Staroverov DB, Chkalina AV, Kotlobay AA, Zvezdova ES, Bochkova AG, Chudakov DM. Single high-dose treatment with glucosaminyl-­muramyl dipeptide is ineffective in treating ankylosing spondylitis. Rheumatol Int. 2011;31(8):1101-3. doi: 10.1007/s00296-010-1663-3Williamson D, Chawla M, R Marks. GMDP for psoriasis. The Lancet.1998;352(9127):545. doi: https://doi.org/10.1016/S0140-6736(05)79253-9Guryanova SV, Kataeva A. Inflammation Regulation by Bacterial Molecular Patterns. Biomedicines. 2023;11(1):183. https://doi.org/10.3390/biomedicines11010183Cheng WC, You TY, Teo ZZ, Sayyad AA, Maharana J, Guo CW, Liang PH, Lin CS, Meng FC. Further Insights on Structural Modifications of Muramyl Dipeptides to Study the Human NOD2 Stimulating Activity. Chem Asian J. 2020;15(22):3836-3844. doi: 10.1002/asia.202001003Mhamane TB, Sambyal S, Vemireddy S, Paturu RSR, Katragadda SB, Syed S, Khan A, Halmuthur M SK. Design, synthesis and biological evaluation of novel lipophilic 2, 5-disubstituted tetrazole analogues of muramyl dipeptide as NOD2 agonists. Bioorg Med Chem. 2023;88-89:117296. doi: 10.1016/j.bmc.2023.117296Reddy PRS, Sambyal S, Mhamane TB, Sravanthi V, Shafi S, Khan IA, Sampath Kumar HM. Synthesis and biological evaluation of novel 2-azido muramyl dipeptide as NOD2 agonistic adjuvants. Bioorg Med Chem. 2022;66:116781. doi: 10.1016/j.bmc.2022.116781Chen K, Huang D, Chiu C, Lin WW. Synthesis of Diverse N-Substituted Muramyl Dipeptide Derivatives and Their Use in a Study of Human NOD2 Stimulation Activity. Chemistry. A European journal. 2015;21(34):11984-11988. https://doi.org/10.1002/chem.201501557Rostovtseva LI, Andronova TM, Malkova VP. Synthesis and antitumor action of glycopeptides containing N-acetylglucosaminyl-(β1-4)-N-acetylmuramyl-­disaccharide unit. Bioorganic Chemistry. 1981;7(12):1843-1858. (in Russian) [Ростовцева Л.И., Андронова Т.М., Малькова В.П. Синтез и противоопухолевое действие гликопептидов, содержащих N-ацетилглюкозаминил-(β1-4)-N-ацетилмурамил-­дисахаридное звено. // Биоорганическая химия. 1981. Т. 7. № 12. С. 1843-1858].Aasen AO, Wang JE. Mediator responses in surgical infections. Surg Infect. 2006;7(Suppl 2): S3-4. doi: 10.1089/sur.2006.7.s2Jin H, Li M, Jeong E. A body-brain circuit that regulates body inflammatory responses. Nature. 2024;630:695-703. https://doi.org/10.1038/s41586-024-07469-yGuryanova 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/life12020192York AG, Skadow MH, Oh J, Qu R, Zhou QD, Hsieh WY, Mowel WK, Brewer JR, Kaffe E, Williams KJ, Kluger Y, Smale ST, Crawford JM, Bensinger SJ, Flavell RA. IL-10 constrains sphingolipid metabolism to limit inflammation. Nature. 2024;627(8004):628-635. doi: 10.1038/s41586-024-07098-5Carlini V, Noonan DM, Abdalalem E, Goletti D, Sansone C, Calabrone L, Albini A. The multifaceted nature of IL-10: regulation, role in immunological homeostasis and its relevance to cancer, COVID-19 and post-­COVID conditions. Front Immunol. 2023;14:1161067. doi: 10.3389/fimmu.2023.1161067Ethuin F, Delarche C, Gougerot-­Pocidalo MA. Regulation of Interleukin 12 p40 and p70 Production by Blood and Alveolar Phagocytes During Severe Sepsis. Lab Invest. 2003;83:1353-1360. https://doi.org/10.1097/01.LAB.0000087589.37269.FCJeong B, Pahan K. IL-12p40 Monomer: A Potential Player in Macrophage Regulation. Immuno. 2024;4(1):77-90. https://doi.org/10.3390/immuno4010005Landoni E, Woodcock MG, Barragan G, Casirati G, Cinella V, Stucchi S, Flick LM, Withers TA, Hudson H, Casorati G, Dellabona P, Genovese P, Savoldo B, Metelitsa LS, Dotti G. IL-12 reprograms CAR-expressing natural killer T cells to long-lived Th1-polarized cells with potent antitumor activity. Nat Commun. 2024;15(1):89. doi: 10.1038/s41467-023-44310-yGuryanova SV, Kozlov IG, Meshcheryakova EA, Alekseeva LG, Andronova TM. Investigation into the influence of glucosaminylmuramyl dipeptide on the normalization of Th1/Th2 balance in patients with atopic bronchial asthma. Immunol. 2009;30:305-309. (In Russian) [Гурьянова С.В., Козлов И.Г., Мещерякова Е.А., Алексеева Л.Г., Андронова Т.М. Глюкозаминилмурамилдипептид нормализует баланс Тh1/Th2 при атопической бронхиальной астме. Иммунология. 2009. № 5. С. 305-308].Carson WE, Giri JG, Lindemann MJ, Linett ML, Ahdieh M, Paxton R, Anderson D, Eisenmann J, Grabstein K, Caligiuri MA. Interleukin (IL) 15 is a novel cytokine that activates human natural killer cells via components of the IL-2 receptor. J Exp Med. 1994;180(4):1395-403. doi: 10.1084/jem.180.4.1395Skariah N, James OJ, Swamy M. Signalling mechanisms driving homeostatic and inflammatory effects of interleukin-15 on tissue lymphocytes. Discov Immunol. 2024;3(1): kyae002. doi: 10.1093/discim/kyae002.Hartana CA, Lancien M, Gao C, Rassadkina Y, Lichterfeld M, Yu XG. IL-15-dependent immune crosstalk between natural killer cells and dendritic cells in HIV-1 elite controllers. Cell Rep. 2023;42(12):113530. doi: 10.1016/j.celrep.2023.113530Mantovani A, Gray PA, Van Damme J, Sozzani S. Macrophage-­derived chemokine (MDC). J Leukoc Biol. 2000;68(3):400-4.Godiska R, Chantry D, Raport CJ, Sozzani S, Allavena P, Leviten D, Mantovani A, Gray PW. Human macrophage-­derived chemokine (MDC), a novel chemoattractant for monocytes, monocyte-­derived dendritic cells, and natural killer cells. J Exp Med. 1997;185(9):1595-604. doi: 10.1084/jem.185.9.1595Chantry D, Romagnani P, Raport CJ, Wood CL, Epp A, Romagnani S, Gray PW. Macrophage-­derived chemokine is localized to thymic medullary epithelial cells and is a chemoattractant for CD3(+), CD4(+), CD8(low) thymocytes. Blood. 1999;94(6):1890-1898.Paul F, Pellegrini S, Uzé G. IFNA2: The prototypic human alpha interferon. Gene. 2015;567(2):132-7. doi: 10.1016/j.gene.2015.04.087Tomasello E, Pollet E, Vu Manh TP, Uzé G, Dalod M. Harnessing Mechanistic Knowledge on Beneficial Versus Deleterious IFN-I Effects to Design Innovative Immunotherapies Targeting Cytokine Activity to Specific Cell Types. Front Immunol. 2014;5:526. doi: 10.3389/fimmu.2014.00526Rizza P, Moretti F, Capone I, Belardelli F. Role of type I interferon in inducing a protective immune response: perspectives for clinical applications. Cytokine Growth Factor Rev. 2015;26(2):195-201. doi: 10.1016/j.cytogfr.2014.10.002Antonelli G, Scagnolari C, Moschella F, Proietti E. Twenty-five years of type I interferon-­based treatment: a critical analysis of its therapeutic use. Cytokine Growth Factor Rev. 2015;26(2):121-31. doi: 10.1016/j.cytogfr.2014.12.006van Boxel-­Dezaire AH, Rani MR, Stark GR. Complex modulation of cell type-specific signaling in response to type I interferons. Immunity. 2006;25(3):361-72. doi: 10.1016/j.immuni.2006.08.014Burnette BC, Liang H, Lee Y, Chlewicki L, Khodarev NN, Weichselbaum RR, Fu YX, Auh SL. The efficacy of radiotherapy relies upon induction of type I interferon-­dependent innate and adaptive immunity. Cancer Res. 2011;71(7):2488-96. doi: 10.1158/0008-5472.CAN-10-2820Ivashkiv LB. IFNγ: signalling, epigenetics and roles in immunity, metabolism, disease and cancer immunotherapy. Nat Rev Immunol. 2018;18(9):545-558. doi: 10.1038/s41577-018-0029-zPrasad KS, Andre P, He M, Bao M, Manganello J, Phillips DR. Soluble CD40 ligand induces beta3 integrin tyrosine phosphorylation and triggers platelet activation by outside-in signaling. Proc Natl Acad Sci USA. 2003;100(21):12367-71. doi: 10.1073/pnas.2032886100Xu, Y., Song, G. The role of CD40-CD154 interaction in cell immunoregulation. J Biomed Sci. 2004;11:426-438. https://doi.org/10.1007/BF02256091Guryanova SV, Sigmatulin IA, Gigani OO, Lipkina SA. Mechanisms of regulation allergic and autoimmune reactions by bacterial origin bioregulators. RUDN Journal of Medicine. 2023;27(4):470-482. doi: 10.22363/2313-0245-2023-27-4-470-48Wicks I, Roberts A. Targeting GM-CSF in inflammatory diseases. Nat Rev Rheumatol. 2016;12:37-48. https://doi.org/10.1038/nrrheum.2015.161Manapova 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). [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; 62 (4): 174-8] doi: 10.18821/0507-4088-2017-62-4-174-178Rechkina 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.Idrose NS, Lodge CJ, Erbas B, Douglass JA, Bui DS, Dharmage SC. A Review of the Respiratory Health Burden Attributable to Short-­Term Exposure to Pollen. Int J Environ Res Public Health. 2022;19(12):7541. doi: 10.3390/ijerph19127541Fussell JC, Kelly FJ. Mechanisms underlying the health effects of desert sand dust. Environ Int. 2021;157:106790. doi:10.1016/j.envint.2021.106790Guryanova SV, Finkina EI, Melnikova DN, Bogdanov IV, Bohle B and Ovchinnikova TV. How Do Pollen Allergens Sensitize? Front. Mol. Biosci. 2022;9:900533. doi: 10.3389/fmolb.2022.900533Ragland SA, Criss AK. From bacterial killing to immune modulation: Recent insights into the functions of lysozyme. PLoS Pathog. 2017;13(9): e1006512. doi: 10.1371/journal.ppat.1006512Guryanova SV, Ferberg AS, Sigmatulin I.A. Inflammatory response modulation by epinephrine and norepinephrine. RUDN Journal of Medicine. 2023;27(3):329-341. doi: 10.22363/2313-0245-2023-27-2-329-341Stafford CA, Gassauer AM, de Oliveira Mann CC, Tanzer MC, Fessler E, Wefers B, Nagl D, Kuut G, Sulek K, Vasilopoulou C, Schwojer SJ, Wiest A, Pfautsch MK, Wurst W, Yabal M, Fröhlich T, Mann M, Gisch N, Jae LT, Hornung V. Phosphorylation of muramyl peptides by NAGK is required for NOD2 activation. Nature. 2022;609(7927):590-596. doi: 10.1038/s41586-022-05125-xGuryanova S, Guryanova A. sbv IMPROVER: Modern approach to systems biology. Methods Mol. Biol. 2017;1613:21-29. doi: 10.1007/978-1-4939-7027-8_270 10цитHoeng J, Boue S, Fields B, Park J, Peitsch MC, Schlage WK, Talikka M, Performers, TCB, 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. F1000Research. 2015;4. https://doi.org/10.12688/f1000research.5984.2Namasivayam AA, Morales AF, Lacave ÁM, Tallam A, Simovic B, Alfaro DG, Bobbili DR, Martin F, Androsova G, Shvydchenko I, Park J, Calvo JV, Hoeng J, Peitsch MC, Racero MG, Biryukov M, Talikka M, Pérez MB, Rohatgi N, Díaz-­Díaz N, Mandarapu R, Ruiz RA, Davidyan S, Narayanasamy S, Boué S, Guryanova S, Arbas SM, Menon S, Xiang Y. Community-­Reviewed Biological Network Models for Toxicology and Drug Discovery Applications. Gene Regul Syst Bio. 2016;10:51-66. doi: 10.4137/GRSB.S39076.Yi M, Li T, Niu M, Zhang H, Wu Y, Wu K, Dai Z. Targeting cytokine and chemokine signaling pathways for cancer therapy. Signal Transduct Target Ther. 2024;9(1):176. doi: 10.1038/s41392-024-01868-3