Analysis of the mechanisms of interaction between the soluble receptor Tas2r1 and lymphocyte transcription factors in various types of bronchial asthma
ORIGINAL PAPERS
Abstract
Introduction. We continue to study the role of ectopic taste receptors in the pathogenesis of bronchial asthma (BA). Previously, an analysis of the association of plasma levels of one of the 25 known subtypes of these receptors Tas2R1 with clinical and functional characteristics of different variants of BA was conducted. The purpose of this article is an additional analysis of possible mechanisms of interaction in BA transcription factors and negative regulators of gene transcription: STAT6, STAT4, T-bet, SOCS1, SOCS3. Materials and methods. The study included 10 practically healthy individuals, 36 patients with allergic bronchial asthma (ABA) and 20 with non-allergic bronchial asthma (NABA). The level of Tas2R1 in the blood serum was determined by the enzyme immunoassay. For the study, lymphocytes from the peripheral blood of healthy individuals and patients with BA, isolated on a density gradient, were used. The methods for determining transcription factors included immunoblotting and RT-PCR. Results. A direct relationship was found between the expression of serum Tas2R1 and an increase in the expression of the transcription factor STAT6, as well as its active form p STAT6 under the action of interleukin 4. In addition, a direct relationship was found between serum Tas2R1 and the factors STAT4 and T-bet. A positive relationship between the Tas2R1 receptor determined in serum and the expression of SOCS1 and SOCS3 molecules can be due to the influence of both STAT6 and STAT4. A negative relationship was found between the expression of serum Tas2R1 and the expression of m RNA of the transcription factor PAX-5 in ABA. The role of the only specific transcription factor for Tas2R receptors — SREBP-2, found in enteroendocrine cells of the STC-1 line of the gastrointestinal tract of mice is discussed. Conclusion. Further study of the putative interactions of the Tas2R1 receptor and lymphocyte transcription factors will allow us to determine in more detail the contribution of ectopic bitter taste receptors to the pathogenesis of BA at the level of the micronetwork of transcription factors.
References
1. Минеев В.Н., Сорокина Л.Н., Нёма М.А. Влияние IL-4 на активность транскрипционного фактора STAT6 в лимфоцитах периферической крови больных бронхиальной астмой. Медицинская иммунология. 2009;11(2-3):177–184. https://doi. org/10.15789/1563-0625-2009-2-3-177-184.
2. Еремеева А.В., Сорокина Л.Н., Минеев В.Н., Лим В.В., Нёма М.А., Трофимов В.И. Экспрессия фактора транскрипции Fox P3 при бронхиальной астме. Медицинская иммунология. 2016;18(4):373–378. https://doi.org/10.15789/1563-0625-2016-4-373-378.
3. Минеев В.Н., Сорокина Л.Н., Нёма М.А., Еремеева А.В. Взаимодействие транскрипционных факторов PAX-5 и STAT6 в патогенезе аллергической бронхиальной астмы. Медицинская иммунология. 2014;16(1):35– 42. https://doi.org/10.15789/1563-0625-2014-1-35-42.
4. Shen C.H., Stavnezer J. Interaction of STAT6 and NF-kappa B: direct association and synergistic activation of interleukin-4-induced transcription. Mol Cell Biol. 1998;18:3395–3404. https://doi.org/10.1128/MCB.18.6.3395.
5. Wei S., Wang M.W., Teitelbaum S.L., Ross F.P. Interleukin-4 reversibly inhibits osteoclastogenesis via inhibition of NF-kappa B and mitogen-activated protein kinase signaling. J Biol Chem. 2002;277(8):6622–6630. https://doi.org/10.1074/jbc.M104957200.
6. Abu-Amer Y. IL-4 abrogates osteoclastogenesis through STAT6-dependent inhibition of NF-kappa B. Clin. Invest. 2001;107(11):1375–1385. https://doi.org/10.1172/JCI10530.
7. Wei S., Sun T., Du J., Zhang B., Xiang D., Li W. Xanthohumol, a prenylated flavonoid from Hops, exerts anticancer effects against gastric cancer in vitro. Oncol Rep. 2018;40(6):3213–3222. https://doi.org/10.3892/or.2018.6723.
8. Kunnimalaiyaan S., Trevino J., Tsai S., Gamblin T.C., Kunnimalaiyaan M. Xanthohumol-Mediated Suppression of Notch1 Signaling Is Associated with Antitumor Activity in Human Pancreatic Cancer Cells. Mol. Cancer Ther. 2015;14(6):1395–1403. https://doi.org/10.1158/1535-7163.MCT-14-0915.
9. Ahmad R., Dalziel J.E. G Protein-Coupled Receptors in Taste Physiology and Pharmacology. Front Pharmacol. 2020;11:587664. https://doi.org/10.3389/fphar.2020.587664.
10. Werry T.D., Wilkinson G.F., Willars G.B. Mechanisms of cross-talk between G-protein-coupled receptors resulting in enhanced release of intracellular Ca2+. Biochem J. 2003;374(Pt 2):281–296. https://doi.org/10.1042/BJ20030312.
11. Selbie L.A., Hill S.J. G protein-coupled-receptor cross-talk: the fine-tuning of multiple receptor-signalling pathways. Trends Pharmacol Sci. 1998;19(3):87–93. https://doi.org/10.1016/s0165-6147(97)01166-8.
12. Jeon T.I., Zhu B., Larson J.L., Osborne T.F. SREBP-2 regulates gut peptide secretion through intestinal bitter taste receptor signaling in mice. J Clin Invest. 2008;118(11):3693–3700. https://doi.org/10.1172/JCI36461.
13. Foster S.R., Porrello E.R., Stefani M., Smith N.J., Molenaar P., dos Remedios C.G., Thomas W.G., Ramialison M. Cardiac gene expression data and in silico analysis provide novel insights into human and mouse taste receptor gene regulation. Naunyn Schmiedebergs Arch Pharmacol. 2015;388(10):1009–1027. https://doi.org/10.1007/s00210-015-1118-1.
14. Castoreno A.B., Wang Y., Stockinger W., Jarzylo L.A., Du H., Pagnon J.C., Shieh E.C., Nohturfft A. Transcriptional regulation of phagocytosis-induced membrane biogenesis by sterol regulatory element binding proteins. Proc Natl Acad.Sci.U S A. 2005;102(37):13129–13134. https://doi.org/10.1073/pnas.0506716102.
15. Fowler J.W.M., Boutagy N.E., Zhang R., Horikami D., Whalen M.B., Romanoski C.E., Sessa W.C. SREBP2 regulates the endothelial response to cytokines via direct transcriptional activation of KLF6. J Lipid Res. 2023;64(8):100411. https://doi.org/10.1016/j.jlr.2023.100411.
16. Wang Y., Yang H., Su X., Cao A., Chen F., Chen P., Yan F., Hu H. SREBP2 promotes the viability, proliferation, and migration and inhibits apoptosis in TGF-β1-induced airway smooth muscle cells by regulating TLR2/NF-κB/NFATc1/ABCA1 regulatory network. Bioengineered. 2022;13(2):3137–3147. https://doi.org/10.1080/21655979.2022.2026550.
17. Нёма М.А., Муркина Р.Г., Садовая В.В., Минеев В.Н. Роль рецепторов Tas2R и транскрипционного фактора SREBP-2 в патогенезе респираторных заболеваний. Новые Санкт-Петербургские врачебные ведомости. 2024;103(4):26–30. https://doi.org/10.24884/1609-2201-2024-103-4-26-30.



