Search for ways to correctthymic dysfunction in rats with experimental diabetes mellitus
Yu.M. Kolesnik, A.M. Kamyshny, A.V. Abramov.
Zaporozhye Medical State University
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Abstract
We investigated the influence of multiple introductions of NO
precursor L-arginine and NOS non-selective blocker N-nitro-
L-arginine (NNLA) on thymic morpho-functional status in
Wistar male rats with experimental diabetes mellitus (EDM).
To reveal insulin-expressing, proliferating, Treg-cells, iNOS+-
cells and Bcl-2+-cells, the immunohistochemical methods of
direct and indirect immunofluorescence with monoclonal anti-
bodies to insulin, PCNA, CD-25 antigen. Bcl-2 and iNOS of
rat were used. It was established that NNLA administration to
rats with EDM has more pronounced effect in comparison
with L-arginine administration, demonstrating an increase in
the number of Treg-cells, insulin-expressing and proliferating
thymocytes and a decrease in the density of iNOS+- and Bcl-
2+-cells population.
References
- Абрамов А.В., Колесник Ю.М., Любомирська В.А., Камишний О.М. Алгоритм автоматичного аналізу лімфоїдної популяції тимуса // Вісн. морфології. –2002. – №2. – С. 261–262.
- Барышников А.Ю., Шишкин Ю.В. Иммунологи- ческие проблемы апоптоза. і – М.: Эдиториал УРСС, 2002. – 320 с.
- Колесник Ю.М, Камышный А.М., Абрамов А.В. Эффекты NO в иммунной системе: NO и тимус // Запорож. мед. журн. – 2006. – №2. – С.5–11.
- Фрейдлин И.С. Регуляторные Т-клетки: происхож- дение и функция // Мед. иммунология. – 2005. – 7, № 4. – С. 347–354.
- Ярилин А.А., Донецкова А.Д. Регуляторные Fохр3+ Т-клетки и их роль при аллергии // Рос. аллергол. журн. – 2005. – № 2. – С. 22–26.
- Bogdan C. The function of nitric oxide in the immune system // Handbook of Exp. Pharmacol. – 2000. – 3. –Р. 443–492.
- Brookes P. Mitochondrial nitric oxide synthase // Mi-tochondrion. – 2004 – 3. – P. 187–204.
- Brune B., Gotz C., Mebmer U. et al. Superoxide for- mation and macrophage resistance to nitric oxide medi-ated apoptosis // J. Biol. Сhem. – 1997 – 272. –P. 7253–7258.
- 9. Brune B., von Knethen A., Sandau K. Nitric oxide and its role in apoptosis // Eur. J. Pharmacol. – 1998 – 351. – P. 261–272.
- 10. Chatenoud L., Bluestone J. CD3-specific antibodies: a portal to the treatment of autoimmunity // Nat. Rev. Immunol. – 2007. – 8. – P.622–632.
- Derbinski J., Gabler J., Kyewski B. Promiscuous gene expression in thymic epithelial cells is regulated at multiple levels // J.Exp. Med. – 2005. – 202. – P.33–45.
- Elfering S., Sarkela T., Giulivi C. Biochemistry of mi- tochondrial nitric oxide synthase // J. Biol. Chem. – 2002. – 277. – P. 38079–38086.
- Flodstrom M., Tyrberg B., Eizirik D., Sandier S. Redu- ced sensitivity of inducible nitric oxide synthase-defi- cient mice to multiple low-dose streptozotocin-induceddiabetes // Diabetes – 1999. – 48. – P. 706–713.
- Geenen V., Brilot F., Louis C. et аl. Importance of a thymus dysfunction in the pathophysiology of type 1 diabetes // Rev. Med. Liege. – 2005. – 60. – №5–6. –P.291–296.
- Giulivi C. Characterization and function of mitochon-drial nitric-oxide synthase. // Free Radical Biol. Med. – 2003. – 34. – P. 397–408.
- Green D., Reed J. Mitochondria and apoptosis // Sci-ence. – 1998. – 281. – P.1309–1312.
- Haluzfk M., Nedveldkovi J. The role of nitric oxide in the development of streptozotocin-induced diabetes mellitus: experimental and clinical implications // Physiol. Res. – 2000. – 49. – P. 37–42.
- Kojima H., Fujimiya M., Matsumura K. et al. Extrapancreatic insulin-producing cells in multiple organs in diabetes // Proc. Natl. Acad. Sci. USA.– 2004.–101.– P. 2458–2463.
- 19. Kroemer G. The proto-oncogene Bcl-2 and its role in regulating apoptosis // Nat. Med. – 1997. – 3. – P.614– 620.
- 20. Lindley S., Dayan C. Defective supressor function in CD4+CD25+T-cells from patients with type 1 diabe- Пошук шляхів корекції дисфункції тимуса
- ISSN 0201-8489 Фізіол. журн., 2008, Т. 54, № 3 35tes // Diabetes. – 2005. – 54. – P. 92–99.
- Luo X., Yang H., Kim I. et al. Systemic transforming grouth factor-beta 1 gene therapy induces Foxp3+ regulatory cells, restores self-tolerance, and facilitates regeneration of beta сell function in overtly diabeticnonobese diabetic mice // Transplantation. – 2005. –79. – P. 1091–1096.
- Mebmer U., Brune B. Nitric oxide-induced apoptosis: p53-dependent and p53-independent signaling path- ways // J. Biochem. – 1996. – 319. – P 299–305.
- Mebmer U., Reed J., Brune B. Bcl-2 protects mac- rophages from nitric oxide-induced apoptosis // J. Biol. Chem. – 1996. – 271. – P. 20192–20197.
- Opferman J., Korsmeyer S. Apoptosis in the develop- ment and maintenance of the immune system // Nat. Immunol. – 2003. – 4. – P.410–415.
- Piccirillo C., Tritt M., Sgouroudis E. et al. Control of type I autoimmune diabetes by naturally occurring CD4+CD25+ regulatory Т lymphocytes in neonatalNOD mice // Ann. N. Y.Acad. Sci. – 2005. – 1051. –P. 72–87.
- Pop S., Wong C., Culton D. et al. Single cell analysis shows decreasing FoxP3 and TGF beta 1 coexpressing CD4+CD25+ regulatory Т cells during autoimmune diabetes // J. Exp. Med. – 2005. – 201. – P. 1333–1346.
- Rietz C., Screpanti V., Brenden N. Overexpression of bcl-2 in T cells affects insulitis in the nonobese dia- betic mouse // Scand. J. Immunol. – 2003. – 57. – №4. –P.342–349.
- Sakaguchi S. Naturally arising CD4+ regulatory Т cells for immunologic self-tolerance and negative control of immune responses // Annu. Rev. Immunol. – 2004. –22. – P. 531–562.
- 29. Sarkela T., Berthiaume J., Elfering S. et al. The modu- lation of oxygen radical production by endogenous ni- tric oxide in mitochondria // J. Biol. Chem. – 2001. –276. – P. 6945–6949.
- 30. Tejedo J., Bernabe J., Ramirez R., Sobrino F. NO in- duces a cGMP-independent release of cytochrome c from mitochondria which precedes caspase 3 activa- tion in insulin producing RINm5F cells // FEBS Lett. –1999. – 459. – P. 238–243.
- Thebault K., Debois D., Vallon-Geoffroy K. et al. Ac- celeration of type 1 diabetes mellitus in proinsulin 2-deficient NOD mice // J. Clin. Invest.– 2003.– 111.–P. 851–857.
- Throsby M., Homo-Delarche F., Chevenne D., Goya R., Dardenne M., Pleau J. Pancreatic hormone expres-sion in the murine thymus: localization in dendritic cells and macrophages // Endocrinology. – 1998. – 139.–P. 2399–2406.
- Trucco M., Giannoukakis N. Immunoregulatory den- dritic cells to prevent and reverse new-onset type 1 diabetes mellitus // Exp. Opin. Biol. Therap. – 2007. –7. – P.951–963.
- Williams O., Norton T., Halligey M. The action of Bax and Bcl-2 on T cell selection // J. Exp. Med. – 1998. – 188. – P.1125–1133.
- Yoshioka Y., Yamamuro A., Maeda S. Nitric oxide at a low concentration protects murine macrophage RAW264 cells against nitric oxide-induced death via cGMP signaling pathway // Brit. J. Pharmacol. – 2003. –139. – P. 28–34.
- Zhang N., Hartig H., Draper D., He Y. The role of apoptosis in the development and function of T lymphocytes // Cell Res. – 2005. – 10. – P.749 – 769
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