Glucocorticoids stimulate the contractile activity of lymphatic vessels and lymph nodes

Objective. The lymphatic network participates in the launch and development of an immune response. From an immunological point of view, the lymph flow, provided by active contractions of the lymphatic vessels, is the process of delivering antigens and antigen-presenting cells to the lymph nodes. The purpose of this study is to study the non-genomic effects and mechanisms of action of glucocorticoids, which are natural immunomodulators, on the transport function of lymphatic vessels and lymph nodes. Materials and methods. Bovine mesenteric afferent lymphatic vessels 1.2-1.5 mm in diameter and lymph nodes were used for the study. The contractile activity of isolated lymphatic vessels and capsules of lymph nodes under the action of glucocorticoids in vitro were studied. Agonists and antagonists of signaling pathways were used to determine the mechanisms of action of glucocorticoids on smooth muscle cells. Results and their discussion. Glucocorticoids in therapeutic concentrations increase the tone of lymphatic vessels and lymph nodes, increase in frequency and a decrease the amplitude of phase contractions. It is shown that glucocorticoids stimulate α-adrenoreceptors of smooth muscle cells due to the increase in their affinity. Glucocorticoids activate in the smooth muscle cells the RhoA / ROCK signaling pathway and inhibit the synthesis of endothelial vasodilators - NO and prostacyclin. The revealed changes in the contractile function of lymphatic vessels and lymph nodes under the action of glucocorticoids underlie the modulation of glucocorticoid transport of lymph and the speed of delivery to the lymph nodes of antigens and antigen-presenting cells, i.e. regulation of immune responses. Conclusions. Non-genomic effects and mechanisms of action of glucocorticoids on the contractile function of lymphatic vessels and nodes have been studied. Glucocorticoids activate smooth muscle cells of lymphatic vessels and nodes by stimulating α-adrenoreceptors, and also inhibit the production of NO and prostacyclin.

лимфатические сосуды, лимфатические узлы, гладкомышечные клетки, эндотелий, глюкокортикоиды, NO, простациклин, lymphatic vessels, lymph nodes, smooth muscle cells, endothelium, glucocorticoids, NO, prostacyclin

1. Борисов А. В. Функциональная анатомия лимфангиона // Морфология. - 2005. - Т. 128. - № 6. - С. 18-27.

2. Лобов Г. И., Орлов Р. С. Клеточные механизмы регуляции транспорта лимфы // Российский физиологический журнал. им. И. М. Сеченова. - 1995. - Т. 81. - № 6. - С. 19-27.

3. Лобов Г. И., Орлов Р. С. Саморегуляция насосной функции лимфангиона // Российский физиологический журнал. им. И. М. Сеченова. - 1988. - Т. 74. - № 7. - С. 977-986.

4. Лобов Г. И., Панькова М. Н. NO-зависимая модуляция сократительной функции гладких мышц капсулы лимфатических узлов // Российский физиологический журнал им. И. М. Сеченова. - 2010. - Т 96. - № 5. - С. 489-497.

5. Лобов Г. И., Панькова М. Н. Транспорт лимфы по лимфатическим узлам: механизмы регуляции // Российский физиологический журнал. им. И. М. Сеченова. - 2012. - Т 98. - № 11. - С. 1350-1361.

6. Acton S. E., Reis E., Sousa C. Dendritic cells in remodeling of lymph nodes during immune responses. Immunol Rev. 2016; 271(1): 221-229. doi: 10.1111/imr.12414.

7. Aird W. C. The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome. Blood. 2003; 101(10): 3765-3777.

8. Allen J. M., McCarron J. G., McHale N. G., Thornbury K. D. Release of [3H]-noradrenaline from the sympathetic nerves to bovine mesenteric lymphatic vessels and its modification by alpha-agonists and antagonists. Br J Pharmacol. 1988; 94(3): 823-833.

9. Boumpas D. T., Chrousos G. P., Wilder R. L. et al. Glucocorticoid therapy for immune-mediated diseases: basic and clinical correlates. Ann Intern Med. 1993; 119(12): 1198-1208.

10. Coutinho A. E, Chapman K. E. The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights. Mol Cell Endocrinol. 2011; 335(1): 2-13. doi: 10.1016/j.mce.2010.04.005.

11. Cruz-Topete D., Cidlowski J. A. One Hormone Two Actions: Anti- and Pro-inflammatory Effects of Glucocorticoids. Neuroimmunomodulation. 2015; 22(1-2): 20-32. doi: 10.1159/000362724.

12. Cyster J. G., Schwab S. R. Sphingosine-1-phosphate and lymphocyte egress from lymphoid organs. Annu Rev Immunol. 2012; 30: 69-94. doi: 10.1146/annurev-immunol-020711-075011.

13. De Bosscher K., Beck I. M., Haegeman G. Classic glucocorticoids versus non-steroidal glucocorticoid receptor modulators: survival of the fittest regulator ofthe immune system? Brain Behav Immun. 2010; 24(7): 1035-42. doi: 10.1016/j.bbi.2010.06.010.

14. Duckles S. P, Miller V. M. Hormonal modulation of endothelial NO production. Pflugers Arch. 2010; 459(6): 841-851. doi: 10.1007/s00424-010-0797-1.

15. Flister M. J., Wilber A., Hall K. L. et al. Inflammation induces lymphangiogenesis through up-regulation of VEGFR-3 mediated by NF-kB and Prox1. Blood. 2010; 115(2): 418-429. doi: 10.1182/blood-2008-12-196840.

16. Grigorova I. L., Panteleev M., Cyster J. G. Lymph node cortical sinus organization and relationship to lymphocyte egress dynamics and antigen exposure. Proc Natl Acad Sci US A. 2010; 107(47): 20447-20452. doi: 10.1073/pnas.1009968107.

17. Haigh R. M., Jones C. T. Effect of glucocorticoids on alpha 1-adrenergic receptor binding in rat vascular smooth muscle. J Mol Endocrinol. 1990(1): 41-48.

18. Holdsworth S. R, Gan P. Y. Cytokines: Names and Numbers You Should Care About. Clin J Am Soc Nephrol. 2015; 10(12): 2243-2254. doi: 10.2215/CJN.07590714.

19. Holstein S. A., Richardson P. G., Laubach J. P., McCarthy P. L. Management of relapsed multiple myeloma after autologous stem cell transplant. Biol Blood Marrow Transplant. 2015; 21(5): 793-798. doi: 10.1016/j.bbmt.2014.12.026.

20. Lee S. R., Kim H. K., Youm J. B. et al. Non-genomic effect of glucocorticoids on cardiovascular system. Pflugers Arch. 2012; 464(6): 549-559. doi: 10.1007/s00424-012-1155-2.

21. Li T., Fang Y., Yang G. et al. The mechanism by which RhoA regulates vascular reactivity after hemorrhagic shock in rats. Am J Physiol Heart Circ Physiol. 2010; 299(2): H292-H299. doi: 10.1152/ajpheart.01031.2009.

22. Puzserova A., Bernatova I. Blood pressure regulation in stress: focus on nitric oxide-dependent mechanisms. Physiol Res. 2016; 65(Suppl. 3): S309-S342.

23. Randolph G. J., Angeli V., Swartz M. A. Dendritic-cell trafficking to lymph nodes through lymphatic vessels. Nat Rev Immunol. 2005; 5(8): 617-628.

24. Roozendaal R., Mempel T. R., Pitcher L. A. et al. Conduits mediate transport of low-molecular-weight antigen to lymph node follicles. Immunity. 2009; 30(2): 264-276. doi: 10.1016/j.immuni.2008.12.014.

25. Spies C. M., Strehl C., van der Goes M. C. et al. Glucocorticoids. Best Pract Res Clin Rheumatol. 2011(6): 891-900. doi: 10.1016/j.berh.2011.11.002.

26. Wallerath T., Godecke A., Molojavyi A. et al. Dexamethasone lacks effect on blood pressure in mice with a disrupted endothelial NO synthase gene. Nitric Oxide. 2004 10(1): 36-41.

27. Webster B., Ekland E. H., Agle L. M. et al. Regulation of lymph node vascular growth by dendritic cells. J Exp Med. 2006; 203(8): 1903-1913.

28. Zawieja D. C. Contractile physiology of lymphatics. Lymphat. Res. Biol. 2009; 7(2): 87-96. doi: 10.1089/lrb.2009.0007.

29. Zen M., Canova M., Campana C. et al. The kaleidoscope of glucorticoid effects on immune system. Autoimmun Rev. 2011; 10(6): 305-310. doi: 10.1016/j.autrev.2010.11.009.

30. Zhang T., Shi W. L., Tasker J. G. et al. Dexamethasone induces rapid promotion of norepinephrine-mediated vascular smooth muscle cell contraction. Mol Med Rep. 2013;.7(2): 549-554. doi: 10.3892/mmr.2012.1196.