{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T05:38:06Z","timestamp":1777268286606,"version":"3.51.4"},"reference-count":39,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2024,10,31]],"date-time":"2024-10-31T00:00:00Z","timestamp":1730332800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"State Assignment of the Ministry of Health of the Russian Federation","award":["056-00119-21-00"],"award-info":[{"award-number":["056-00119-21-00"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Ongoing outbreaks and often rapid spread of infections caused by coronaviruses, influenza, Nipah, Dengue, Marburg, monkeypox, and other viruses are a concern for health authorities in most countries. Therefore, the search for and study of new antiviral compounds are in great demand today. Since almost all viruses with pandemic potential have immunotoxic properties of various origins, particular attention is paid to the search and development of immunomodulatory drugs. We have synthesised a new compound related to indole-3-carboxylic acid derivatives (hereinafter referred to as the XXV) that has antiviral and interferon-inducing activity. The purpose of this work is to study the effect of the XXV on the stimulation of the expression of toll-like receptor genes, interferons, and immunoregulatory cytokines in a macrophage-like cell model. In this study, real-time PCR methods were used to obtain data on the transcriptional activity of genes in macrophage-like cells. Stimulation of the genes of toll-like receptors TLR2, TLR3, TLR4, TLR7, TLR8, and TLR9 was detected. A high-fold increase in stimulation (from 6.5 to 16,000) of the expression of the TLR3 and TLR4 genes was detected after 4 h of exposure to the XXV. Increased activity of interferon (IFNA1, IFNA2, IFNB1, IFNK, and IFN\u03bb1) genes with simultaneous stimulation of the expression of interferon receptor (IFNAR1 and IFNAR2) genes and signalling molecule (JAK1 and ISG15) genes was detected. Increased fold stimulation of the expression of the cytokine genes IL6, TNFA, IL12A, and IL12B was also observed. Thus, it is shown that the XXV is an activator of TLR genes of innate immunity, which trigger signalling mechanisms of pathogen \u201crecognition\u201d and lead to stimulation of the expression of genes of proinflammatory cytokines and interferons.<\/jats:p>","DOI":"10.3390\/v16111718","type":"journal-article","created":{"date-parts":[[2024,10,31]],"date-time":"2024-10-31T06:55:37Z","timestamp":1730357737000},"page":"1718","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Expression of Toll-like Receptor Genes and Antiviral Cytokines in Macrophage-like Cells in Response to Indole-3-carboxylic Acid Derivative"],"prefix":"10.3390","volume":"16","author":[{"given":"Alexander","family":"Narovlyansky","sequence":"first","affiliation":[{"name":"National Research Centre for Epidemiology and Microbiology Named after the Honorary Academician N.F. Gamaleya, Ministry of Health of the Russian Federation, Moscow 123098, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5266-9783","authenticated-orcid":false,"given":"Alexander","family":"Pronin","sequence":"additional","affiliation":[{"name":"National Research Centre for Epidemiology and Microbiology Named after the Honorary Academician N.F. Gamaleya, Ministry of Health of the Russian Federation, Moscow 123098, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vladislav","family":"Poloskov","sequence":"additional","affiliation":[{"name":"National Research Centre for Epidemiology and Microbiology Named after the Honorary Academician N.F. Gamaleya, Ministry of Health of the Russian Federation, Moscow 123098, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander","family":"Sanin","sequence":"additional","affiliation":[{"name":"National Research Centre for Epidemiology and Microbiology Named after the Honorary Academician N.F. Gamaleya, Ministry of Health of the Russian Federation, Moscow 123098, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7346-5536","authenticated-orcid":false,"given":"Marina","family":"Mezentseva","sequence":"additional","affiliation":[{"name":"National Research Centre for Epidemiology and Microbiology Named after the Honorary Academician N.F. Gamaleya, Ministry of Health of the Russian Federation, Moscow 123098, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Irina","family":"Fedyakina","sequence":"additional","affiliation":[{"name":"National Research Centre for Epidemiology and Microbiology Named after the Honorary Academician N.F. Gamaleya, Ministry of Health of the Russian Federation, Moscow 123098, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Irina","family":"Suetina","sequence":"additional","affiliation":[{"name":"National Research Centre for Epidemiology and Microbiology Named after the Honorary Academician N.F. Gamaleya, Ministry of Health of the Russian Federation, Moscow 123098, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Igor","family":"Zubashev","sequence":"additional","affiliation":[{"name":"National Research Centre for Epidemiology and Microbiology Named after the Honorary Academician N.F. Gamaleya, Ministry of Health of the Russian Federation, Moscow 123098, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Felix","family":"Ershov","sequence":"additional","affiliation":[{"name":"National Research Centre for Epidemiology and Microbiology Named after the Honorary Academician N.F. Gamaleya, Ministry of Health of the Russian Federation, Moscow 123098, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9690-4746","authenticated-orcid":false,"given":"Marina","family":"Filimonova","sequence":"additional","affiliation":[{"name":"A. Tsyb Medical Radiological Research Center\u2014Branch of the National Medical Research Radiological Center of the Ministry of Health of the Russian Federation, Obninsk 249036, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valentina","family":"Surinova","sequence":"additional","affiliation":[{"name":"A. Tsyb Medical Radiological Research Center\u2014Branch of the National Medical Research Radiological Center of the Ministry of Health of the Russian Federation, Obninsk 249036, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Irina","family":"Volkova","sequence":"additional","affiliation":[{"name":"A. Tsyb Medical Radiological Research Center\u2014Branch of the National Medical Research Radiological Center of the Ministry of Health of the Russian Federation, Obninsk 249036, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Egor","family":"Bogdanov","sequence":"additional","affiliation":[{"name":"Faculty of Biotechnology, Lomonosov Moscow University of Fine Chemical Technology, Moscow 119571, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,31]]},"reference":[{"key":"ref_1","unstructured":"(2024, August 28). Available online: https:\/\/www.who.int\/ru\/emergencies\/disease-outbreak-news."},{"key":"ref_2","unstructured":"(2024, August 14). (In Russian)."},{"key":"ref_3","unstructured":"Lvov, D.K. (2013). Handbook of Virology. Viruses and Viral Infections of Humans and Animals, Publishing House \u201cMedical Information Agency\u201d. (In Russian)."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1146\/annurev-immunol-032414-112240","article-title":"Innate immune pattern recognition: A cell biological perspective","volume":"33","author":"Brubaker","year":"2015","journal-title":"Annu. Rev. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e549","DOI":"10.1002\/mco2.549","article-title":"Toll-like receptors in health and disease","volume":"5","author":"Wang","year":"2024","journal-title":"MedComm"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1089\/jir.2010.0095","article-title":"Toll-like receptors as interferon regulated genes and their role in disease","volume":"31","author":"Khoo","year":"2011","journal-title":"J. Interferon Cytokine Res."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Aluri, J., Cooper, M.A., and Schuettpelz, L.G. (2021). Toll-Like Receptor Signaling in the Establishment and Function of the Immune System. Cells, 10.","DOI":"10.3390\/cells10061374"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1016\/j.cell.2020.02.041","article-title":"Toll-like Receptors and the Control of Immunity","volume":"180","author":"Fitzgerald","year":"2020","journal-title":"Cell"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Zhang, H., Kang, L., Yao, H., He, Y., Wang, X., Xu, W., Song, Z., Yin, Y., and Zhang, X. (2016). Streptococcus pneumoniae Endopeptidase O (PepO) Elicits a Strong Innate Immune Response in Mice via TLR2 and TLR4 Signaling Pathways. Front. Cell. Infect. Microbiol., 6.","DOI":"10.3389\/fcimb.2016.00023"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"333","DOI":"10.5114\/ceji.2016.65131","article-title":"Expression of surface and intracellular Toll-like receptors by mature mast cells","volume":"41","author":"Agier","year":"2016","journal-title":"Cent. Eur. J. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1631\/jzus.B2000808","article-title":"Toll-like receptor 3 (TLR3) regulation mechanisms and roles in antiviral innate immune responses","volume":"22","author":"Chen","year":"2021","journal-title":"J. Zhejiang Univ. Sci. B"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1016\/j.immuni.2016.09.011","article-title":"Structural Analysis Reveals that Toll-like Receptor 7 Is a Dual Receptor for Guanosine and Single-Stranded RNA","volume":"45","author":"Zhang","year":"2016","journal-title":"Immunity"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Patamawenu, A.A., Wright, N.E., Shofner, T., Evans, S., Manion, M.M., Doria-Rose, N., Migueles, S.A., Mendoza, D., Peterson, B., and Wilhelm, C. (2019). Toll-like receptor 7-adapter complex modulates interferon-\u03b1 production in HIV-stimulated plasmacytoid dendritic cells. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0225806"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.1016\/j.cell.2019.11.001","article-title":"TLR8 Is a Sensor of RNase T2 Degradation Products","volume":"179","author":"Greulich","year":"2019","journal-title":"Cell"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"11416","DOI":"10.1073\/pnas.0403555101","article-title":"Herpes simplex virus type-1 induces IFN-alpha production via Toll-like receptor 9-dependent and -independent pathways","volume":"101","author":"Hochrein","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","unstructured":"Filimonova, M.V., Tsyshkova, N.G., Narovlyansky, A.N., Marinchenko, V.P., Koval, L.S., Parfenova, T.M., Izmestieva, A.V., and Ershov, F.I. (2015). Indole-3-Carboxylic Acid Derivatives with Antiviral Activity. (2552422 C2), Patent RU, (In Russian)."},{"key":"ref_17","unstructured":"Narovlyansky, A.N., Filimonova, M.V., Tsyshkova, N.G., Pronin, A.V., Grebennikova, T.V., Karamov, E.V., Larichev, V.F., Kornilaeva, G.V., Fedyakina, I.T., and Dolzhikova, I.V. (2022). Indole-3-Carboxylic Acid Derivative with Antiviral Activity Against SARS-CoV-2. (Application No. 2022133152\/04(072130)), (In Russian)."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"83","DOI":"10.32607\/actanaturae.26623","article-title":"In Vitro Antiviral Activity of a New Indol-3-carboxylic Acid Derivative Against SARS-CoV-2","volume":"15","author":"Narovlyansky","year":"2023","journal-title":"Acta Naturae"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"28","DOI":"10.17650\/1726-9784-2016-15-3-28-33","article-title":"The effect of interferons and interferon inducers on the expression of TLR\/RLR receptor genes and differentiation of tumor cell lines THP-1 and HCT-116","volume":"15","author":"Sokolova","year":"2016","journal-title":"Russ. J. Biother."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"60","DOI":"10.17650\/1726-9784-2019-18-1-60-66","article-title":"Signaling TLR\/RLR mechanisms of immunomodulatory action of the drugs Ingavirin and Thymogen","volume":"18","author":"Sokolova","year":"2019","journal-title":"Russ. J. Biother."},{"key":"ref_21","first-page":"26","article-title":"Stimulation of signal transduction genes by Ridostin, Cycloferon and Ingavirin","volume":"14","author":"Sokolova","year":"2015","journal-title":"Cytokines Inflamm."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"116","DOI":"10.30895\/2221-996X-2021-21-2-116-121","article-title":"Effect of Kagocel\u00ae on the expression of Toll-like receptor genes of the innate immune system in human THP-1 monocytes with different levels of differentiation. BIOpreparations","volume":"21","author":"Sokolova","year":"2021","journal-title":"Prev. Diagn. Treat."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1002\/ijc.2910260208","article-title":"Establishment and characterization of a human acute monocytic leukemia cell line (THP-1)","volume":"26","author":"Tsuchiya","year":"1980","journal-title":"Int. J. Cancer"},{"key":"ref_24","unstructured":"(2024, August 29). Human Monocytes with Reduced NLRP3 Activity. Available online: https:\/\/www.invivogen.com\/sites\/default\/files\/invivogen\/products\/files\/thp1_defnlrp3_tds.pdf."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/0022-1759(83)90303-4","article-title":"Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays","volume":"65","author":"Mosmann","year":"1983","journal-title":"J. Immunol. Methods"},{"key":"ref_26","unstructured":"Khabriev, R.U. (2005). Manual on Experimental (Preclinical) Study of New Pharmacological Substances, Meditsina. (In Russian)."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"110","DOI":"10.3892\/or.2022.8321","article-title":"Interferon-stimulated gene 15 promotes progression of endometrial carcinoma and weakens antitumor immune response","volume":"47","author":"Zhao","year":"2022","journal-title":"Oncol. Rep."},{"key":"ref_28","unstructured":"(2024, October 24). ISG15 Gene-ISG15 Ubiquitin Like Modifier. Gene Cards. The Human Gene Database. Updated: 6 August 2024. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=ISG15#summaries."},{"key":"ref_29","unstructured":"(2024, October 24). Wikipedia-ISG15. Available online: https:\/\/en.wikipedia.org\/wiki\/ISG15."},{"key":"ref_30","unstructured":"(2024, October 24). Interleukin 1 Receptor Associated Kinase 3. Gene Cards. The Human Gene Database. Updated: 6 August 2024. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=IRAK3."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.jim.2013.11.006","article-title":"Reduced PMA enhances the responsiveness of transfected THP-1 macrophages to polarizing stimuli","volume":"402","author":"Wittig","year":"2014","journal-title":"J. Immunol. Methods"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.jim.2016.01.012","article-title":"The choice of phorbol 12-myristate 13-acetate differentiation protocol influences the response of THP-1 macrophages to a pro-inflammatory stimulus","volume":"430","author":"Lund","year":"2016","journal-title":"J. Immunol. Methods"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Nguyen, T.H., Turek, I., Meehan-Andrews, T., Zacharias, A., and Irving, H. (2020). Analysis of interleukin-1 receptor associated kinase-3 (IRAK3) function in modulating expression of inflammatory markers in cell culture models: A systematic review and meta-analysis. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0244570"},{"key":"ref_34","first-page":"161","article-title":"The effect of mitogens on the differentiation of THP-1 cells and the expression of TLR\/RLR genes","volume":"15","author":"Poloskov","year":"2016","journal-title":"Cytokines Inflamm."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1056\/NEJM200008033430506","article-title":"Innate immunity","volume":"343","author":"Medzhitov","year":"2000","journal-title":"N. Engl. J. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1038\/41131","article-title":"A human homologue of the Drosophila Toll protein signals activation of adaptive immunity","volume":"388","author":"Medzhitov","year":"1997","journal-title":"Nature"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1517\/13543776.2014.880691","article-title":"Toll-like receptor agonists: A patent review (2011\u20132013)","volume":"24","author":"Hussein","year":"2014","journal-title":"Expert Opin. Ther. Pat."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3882","DOI":"10.1038\/s41467-024-48073-y","article-title":"TLR agonists polarize interferon responses in conjunction with dendritic cell vaccination in malignant glioma: A randomized phase II Trial","volume":"15","author":"Everson","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2938","DOI":"10.1021\/acs.jmedchem.8b01583","article-title":"Structural basis of TLR2\/TLR1 activation by the synthetic agonist Diprovocim","volume":"62","author":"Su","year":"2019","journal-title":"J. Med. Chem."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/16\/11\/1718\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:25:22Z","timestamp":1760113522000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/16\/11\/1718"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,31]]},"references-count":39,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2024,11]]}},"alternative-id":["v16111718"],"URL":"https:\/\/doi.org\/10.3390\/v16111718","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,31]]}}}