IMPACT OF NITRIC OXIDE SYNTHESIS MODULATORS ON THE CYTOKINES PROFILE IN EXPERIMENTAL ANTIPHOSPHOLIPID SYNDROME
Background. Antiphospholipid syndrome (APS) is an autoimmune disease characterized by the presence of specific antibodies.
Objective. The aim of the study was to investigate the effect of combined use of L-arginine and aminoguanidine on cytokine profile (IL-1β, IL-6, TNF-α, IL-4, IL-10) in experimental APS.
Methods. The study was performed on BALB/c female mice. L-arginine (25 mg/kg) and aminoguanidine (10 mg/kg) were used for correction. Serum cytokines concentrations were assessed using an ELISA test.
Results. It was found that in APS the concentration of proinflammatory cytokines IL-1β, IL-6 and TNF-a increases in 3.2, 2.3 and 4.5 times respectively, compare to the control. At the same time a decrease of the IL-4 and IL-10 in 1.9 and 2.2 times was evidenced.
Aminoguanidine, a selective iNOS inhibitor, caused a significant decrease of TNF-α by 57% (p<0.001), but there were no changes in IL-1β, IL-6, IL-4 and IL-10 compare to the APS-group. L-arginine combined with aminoguanidine caused a significant decrease in the concentration of IL-1β by 30% (p<0.01), IL-6 – by 16% (p<0.05), TNF-a – by 59% (p<0.001) compare to the control. At the same time, the concentration of IL-4 increased by 35% (p <0.01), IL-10 – by 25% (p<0.005).
Conclusions. Combined use of the precursor of the NO synthesis L-arginine and aminoguanidine, a selective iNOS inhibitor, leads to a decrease in the concentrations of IL-1β, IL-6, TNF-a and an increase of IL-4 and IL-10 compare to the group of the BALB/c mice with APS and the group of animals administered with aminoguanidine.
Khangura RK, Cooper S, Luo GY. Antiphospholipid Antibody Syndrome: Pathogenesis, Diagnosis, and Management in Pregnancy. Maternal-Fetal Medicine. 2019 Jul 1;1(1):38-42.
Ahluwalia J, Sreedharanunni S. The Laboratory Diagnosis of the Antiphospholipid Syndrome. Indian Journal of Hematology and Blood Transfusion. 2017 Mar 1;33(1):8-14.
Bitsadze VO, Khizroeva DKh, Idrisova LE, etc. Catastrophic antiphospholipid syndrome. Pathogenesis. Obstetrics, Gynecology and Reproduction. 2015;2:32-53. (In Russian)
Velásquez M, Rojas M, Abrahams VM, Escudero C, Cadavid ÁP. Mechanisms of Endothelial Dysfunction in Antiphospholipid Syndrome: Association with Clinical Manifestations. Frontiers in Physiology. 2018;9:1840.
D'Angelo C, Franch O, Fernández Paredes L, Oreja-Guevara C, Núñez-Beltrán M, Comins A, Reale M, Sánchez-Ramón S. Antiphospholipid Antibodies overlapping in Isolated Neurological Syndrome and Multiple Sclerosis: Neurobiological Insights and Diagnostic Challenges. Frontiers in Cellular Neuroscience. 2019;13:107.
Seredavkina NV, Reshetnyak TM, Aleksandrova EN and others. Marker of inflammation in patients with antiphospholipid syndrome with cardiovascular pathology. Scientific and Practical Rheumatology. 2010;5:37-43. (In Russian)
McDonnell T, Wincup C, Buchholz I, Pericleous C, Giles I, Ripoll V, Cohen H, Delcea M, Rahman A. The role of beta-2-glycoprotein I in health and disease associating structure with function: more than just APS. Blood reviews. 2019 Aug 16:100610.
Berman J, Girardi G, Salmon J.E. TNF-alpha is a critical effector and a target for therapy in antiphospholipid antibody-induced pregnancy loss. J. Immunol. 2005; 174: 485-90.
Shoenfeld Y, Meroni PL, Cervera R. Antiphospholipid syndrome dilemmas still to be solved: 2008 status. Annals of the rheumatic diseases. 2008 Apr 1;67(4):438-42.
Madej PD, Piecha D, Pluta B, Zubelewicz-Szkodzinska, Havrylyuk A, Kondratyuk M, et al. Immunological factors in etiopathogenesis of recurrent miscarriages. Lviv Medical Journal. 2015;3:89-95. (In Ukrainian)
Menachem A, Chapman J, Katzav A. Significant changes in the levels of secreted cytokines in brains of experimental antiphospholipid syndrome mice. Autoimmune diseases. 2012;2012:404815.
Soltesz P, Der H, Veres K, Laczik R, Sipka S, Szegedi G, et al. Immunological features of primary anti-phospholipid syndrome in connection with endothelial dysfunction. Rheumatology. 2008;47: 1628-34.
Cella M, Farina MG, Dominguez Rubio AP, Di Girolamo G, Ribeiro ML, Franchi AM. Dual effect of nitric oxide on uterine prostaglandin synthesis in a murine model of preterm labour. British Journal of Pharmacology. 2010 Oct;161(4):844-55.
Zaichenko GV, Laryanovskaya YB, Deeva TV. etc. Morphological status of uterus and placenta in experimental modeling of gestational antiphospholipid syndrome in mice. Ukrainian Medical Almanac. 2011;14(4):136–41. (In Ukrainian)
Swadzba J, Iwaniec T, Musial J. Increased level of tumor necrosis factor-α in patients with antiphospholipid syndrome: marker not only of inflammation but also of the prothrombotic state. Rheumatology International. 2011 Mar 1;31(3):307-13.
Suprun EV, Chekman IS, Belenichev IF and others. Cytokine therapy in the complex treatment of cerebrovascular diseases: state, prospects for research. Rational pharmacotherapy. 2017;1(42):19-31. http://rpht.com.ua/ua-issue-article-1610. (In Ukrainian).
Farzaneh-Far A, Roman MJ, Lockshin MD, Devereux RB, Paget SA, Crow MK et al. Relationship of antiphospholipid antibodies to cardiovascular manifestations of systemic lupus erythematosus. Arthritis & Rheumatism: Official Journal of the American College of Rheumatology. 2006 Dec;54(12):3918-25.
Forastiero RR, Martinuzzo ME, De Larranaga GF. Circulating levels of tissue factor and proinflammatory cytokines in patients with primary antiphospholipid syndrome or leprosy related antiphospholipid antibodies. Lupus. 2005 Feb;14(2):129-36.
Falcon BB. Neuroinflammation in the biochemical mechanisms of amyloidosis. Bulletin of the VN Kharkiv National University Karazin. Biology series. 2008;30:103-12. (In Ukrainian).
Yılmaz BD, Genç H, Baysal B, Eren B. The Protective Effect of Amino-guanidine, an Inducible Nitric Oxide Synthase Inhibitor, on Aluminium Sulphate Neuro-toxicity in the Rat (Wistar albino) Cerebellar Purkinje Cells: Stereological Study. Middle Black Sea Journal of Health Science. 2017;3(3):7-14.
Salim T, Sershen CL, May EE. Investigating the role of TNF-α and IFN-γ activation on the dynamics of iNOS gene expression in LPS stimulated macrophages. PloS one. 2016 Jun 8;11(6):e0153289.
hang GL, Wang YH, Teng HL, Lin ZB. Effects of aminoguanidine on nitric oxide production induced by inflammatory cytokines and endotoxin in cultured rat hepatocytes. World journal of gastroenterology. 2001 Jun 15;7(3):331-4.
Ferreira EI, Serafim RA. Nitric Oxide Synthase Inhibitors. Nitric Oxide Synthase: Simple Enzyme-Complex Roles. 2017 May 17:217.
Lopez-Pedrera C, Aguirre MA, Ruiz-Limon P, Perez-Sanchez C, Jimenez-Gomez Y, Barbarroja N, Cuadrado MJ. Immunotherapy in antiphospholipid syndrome. International immunopharmacology. 2015 Aug 1;27(2):200-8.
Sheybak VM, Pavlyukovets AJ. Arginine and the immune system are possible mechanisms of interaction. Bulletin of the Vitebsk State Medical University. 2013;12(1):6-13. (In Russian)
Stepanov YM, Kononov IN, Zhurbina AI et al. Arginine in medical practice (review). Journal of the Academy of Medical Sciences of Ukraine. 2004;10(1): 340-52. (In Russian)
Howes A, Taubert C, Blankley S, Spink N, Wu X, Graham CM, Zhao J, Saraiva M, Ricciardi-Castagnoli P, Bancroft GJ, O’Garra A. Differential production of type I IFN determines the reciprocal levels of IL-10 and proinflammatory cytokines produced by C57BL/6 and BALB/c macrophages. The Journal of Immunology. 2016 Oct 1;197(7):2838-53.
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