EFFECTS OF STATINS AND OTHER BIOLOGICAL PREPARATIONS UPON ACTIVATION OF MITOGEN-ACTIVATED PROTEIN KINASES IN PATIENTS WITH RHEUMATOID ARTHRITIS
https://doi.org/10.15789/1563-0625-2009-1-71-78
Abstract
Abstract. In this study, we evaluated effects of statins and other biological preparations upon spontaneous and stimulated activation of МАРК p38 and ERK1/2 in monocytes from the patients with rheumatoid arthritis (RA). We used peripheral blood mononuclear cells (PBMC) from RA patients and healthy donors. PBMC were cultured in presence of 0, 0.1, 1 or 10 мM mevastatin, 10 мg/ml IL-1 receptor antagonist (IL-1Ra), 5 мg/ml infliximab, and 5 мg/ml soluble pegylated p55 TNF-receptor (r-met-Hu-sTNF-RI). To study the mechanisms of mevastatin effects upon МАРК p38 and ERK1/2 activities, L-mevalonate was added to the cultures. The cells were stained with anti-phospho-MAPK p38, or anti-phospho-ERK1/2, and analyzed with flow cytometry. We have shown that IL-1Ra and r-met-Hu-sTNF-RI inhibited spontaneous MAPK р38 activation. Mevastatin reduced spontaneous MAPK p38 and ERK1/2 phosphorylation. Mevastatininduced suppression of MAPK p38 and ERK1/2 activation was not dose-dependent. L-mevalonate completely prevented mevastatin-induced reduction of MAPK р38 phosphorylation and partially reversed inhibition of МАРК ERK1/2. In conclusion, decrease in MAPK activation represents a common mechanism of anti-inflammatory effects exerted by statins and some other biologicals.
About the Authors
I. V. Shirinsky
ГУ НИИ клинической иммунологии СО РАМН, г. Новосибирск
Russian Federation
Russian Federation
V. A. Kozlov
ГУ НИИ клинической иммунологии СО РАМН, г. Новосибирск
Russian Federation
Competing Interests: лаборатория регуляции иммунопоэза
Russian Federation
Competing Interests: лаборатория регуляции иммунопоэза
V. S. Shirinsky
ГУ НИИ клинической иммунологии СО РАМН, г. Новосибирск
Russian Federation
Russian Federation
References
1. Ширинский И.В., Малышева О.А., Ширинский В.С. Цитокиновая и антицитокиновая терапия ревматоидного артрита и рассеянного склероза//Медицинская иммунология. -2001. -№ 3. -С. 401-414.
2. Ширинский И.В., Желтова О.И., Соловьева Н.Ю., Ширинский В.С., Козлов В.А. Клиническая эффективность статинов при ревматоидном артрите -пилотное исследование//Медицинская иммунология. -2007. -№ 4-5. -С. 505-508.
3. Arnett F.C., Edworthy S.M., Bloch D.A., McShane D.J., Fries J.F., Cooper N.S., Healey L.A.,Kaplan S.R., Liang M.H., Luthra H.S., et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis//Arthritis Rheum. -1988. -Vol. 31. -P. 315-324.
4. Boyum A. Isolation of leucocytes from human blood. A two-phase system for removal of red cells with methylcellulose as erythrocyte-aggregating agent//Scand. J. Clin. Lab. Invest., Suppl. -1968. -Vol. 97. -P. 9-29.
5. Edwards C.K., 3rd. PEGylated recombinant human soluble tumour necrosis factor receptor type I (r-Hu-sTNF-RI): novel high affinity TNF receptor designed for chronic inflammatory diseases//Ann. Rheum. Dis.-1999. -Vol. 58, Suppl. 1. -P. I73-181.
6. Fabris M., Tolusso B., Di Poi E., Tomietto P., Sacco S., Gremese E., Ferraccioli G. Mononuclear cell response to lipopolysaccharide in patients with rheumatoid arthritis: relationship with tristetraprolin expression//J. Rheumatol. -2005. -Vol. 32. -P. 998-1005.
7. Forrest C.M., Harman G., McMillan R.B., Stoy N., Stone T.W., Darlington L.G. Modulation of cytokine release by purine receptors in patients with rheumatoid arthritis//Clin. Exp. Rheumatol. -2005. -Vol. 23. -P. 89-92.
8. Gallin J., Snyderman R., Agents targeting transcription factors//Inflammation/ed. Fearon D.T., Barton F.H., Nathan C., Lippincot Williams & Wilkins, 1999. -P. 1159-1176.
9. Gao B., Calhoun K., Fang D. The proinflammatory cytokines IL-1beta and TNF-alpha induce the expression of Synoviolin, an E3 ubiquitin ligase, in mouse synovial fibroblasts via the Erk1/2-ETS1 pathway//Arthritis Res Ther. -2006. -Vol. 8. -P. R172.
10. Greenwood J., Steinman L., Zamvil S.S. Statin therapy and autoimmune disease: from protein prenylation to immunomodulation//Nat. Rev. Immunol. -2006. -Vol. 6. -P. 358-370.
11. Kanda H., Hamasaki K., Kubo K., Tateishi S., Yonezumi A., Kanda Y., Yamamoto K., Mimura T.Antiinflammatory effect of simvastatin in patients with rheumatoid arthritis//J. Rheumatol. -2002. -Vol. 29. -P. 2024-2026.
12. Kinne R.W., Brauer R., Stuhlmuller B., Palombo-Kinne E., Burmester G.R. Macrophages in rheumatoid arthritis//Arthritis Res. -2000. -Vol. 2. -P. 189-202.
13. Lazzerini P.E., Lorenzini S., Selvi E., Capecchi P.L., Chindamo D., Bisogno S., Ghittoni R., Natale M.R.,Caporali F., Giuntini S., Marcolongo R., Galeazzi M., Laghi-Pasini F. Simvastatin inhibits cytokine production and nuclear factor-kB activation in interleukin 1beta-stimulated synoviocytes from rheumatoid arthritis patients//Clin. Exp. Rheumatol. -2007. -Vol. 25. -P. 696-700.
14. Li M., Liu Y., Dutt P., Fanburg B.L., Toksoz D. Inhibition of serotonin-induced mitogenesis, migration, and ERK MAPK nuclear translocation in vascular smooth muscle cells by atorvastatin//Am J Physiol Lung Cell Mol Physiol. -2007. -Vol. 293. -P. L463-471.
15. Lim L., Manser E., Leung T., Hall C. Regulation of phosphorylation pathways by p21 GTPases. The p21 Ras-related Rho subfamily and its role in phosphorylation signalling pathways//Eur. J. Biochem. -1996. -Vol. 242. -P. 171-185.
16. Liote F., Boval-Boizard B., Weill D.,Kuntz D., Wautier J.L. Blood monocyte activation in rheumatoid arthritis: increased monocyte adhesiveness, integrin expression, and cytokine release//Clin. Exp. Immunol. -1996. -Vol. 106. -P. 13-19.
17. Loetscher H., Gentz R., Zulauf M., Lustig A., Tabuchi H., Schlaeger E.J., Brockhaus M., Gallati H.,Manneberg M., Lesslauer W. Recombinant 55-kDa tumor necrosis factor (TNF) receptor. Stoichiometry of binding to TNF alpha and TNF beta and inhibition of TNF activity//J. Biol. Chem. -1991. -Vol. 266. -P. 18324-18329.
18. McCarey D.W., McInnes I.B., Madhok R., Hampson R., Scherbakov O., Ford I., Capell H.A., Sattar N. Trial of Atorvastatin in Rheumatoid Arthritis (TARA): double-blind, randomised placebo-controlled trial//Lancet. -2004. -Vol. 363. -P. 2015-2021.
19. Melchert R.B., Liu H., Granberry M.C., Kennedy R.H. Lovastatin inhibits phenylephrineinduced ERK activation and growth of cardiac myocytes//Cardiovasc Toxicol. -2001. -Vol. 1. -P. 237-252.
20. Montag D.T. Successful development of a flow cytometric assay to analyze cytokine-induced phosphorylation pathways [CIPP] within peripheral Терапия РА и активация МАРК blood leukocytes. Dissertation. Pittsburgh. -2003. -P. 123.
21. Rossa C., Ehmann K., Liu M., Patil C., Kirkwood K.L. MKK3/6-p38 MAPK signaling is required for IL-1beta and TNF-alpha-induced RANKL expression in bone marrow stromal cells//J. Interferon Cytokine Res.-2006. -Vol. 26. -P. 719-729.
22. Rossol M., Kaltenhauser S., Scholz R.,Hantzschel H., Hauschildt S., Wagner U. The contact-mediated response of peripheral-blood monocytes to preactivated T cells is suppressed by serum factors in rheumatoid arthritis//Arthritis Res Ther. -2005. -Vol. 7. -P. R1189-1199.
23. Scallon B.J., Trinh H., Nedelman M., Brennan F.M., Feldmann M., Ghrayeb J. Functional comparisons of different tumour necrosis factor receptor/IgG fusion proteins//Cytokine. -1995. -Vol. 7. -P.759-770.
24. Schett G., Zwerina J., Firestein G. The p38 mitogen-activated protein kinase (MAPK) pathway in rheumatoid arthritis//Ann. Rheum. Dis.-2008. -Vol. 67. -P. 909-916.
25. Senokuchi T., Matsumura T., Sakai M., Yano M., Taguchi T., Matsuo T., Sonoda K., Kukidome D., Imoto K., Nishikawa T., Kim-Mitsuyama S., Takuwa Y., Araki E. Statins suppress oxidized low density lipoprotein-induced macrophage proliferation by inactivation of the small G protein-p38 MAPK pathway//J. Biol. Chem. -2005. -Vol. 280. -P. 6627-6633.
26. Shinohara S., Hirohata S., Inoue T., Ito K. Phenotypic analysis of peripheral blood monocytes isolated from patients with rheumatoid arthritis//J. Rheumatol. -1992. -Vol. 19. -P.211-215.
27. Stuhlmuller B., Ungethum U., Scholze S., Martinez L., Backhaus M., Kraetsch H.G., Kinne R.W.,Burmester G.R. Identification of known and novel genes in activated monocytes from patients with rheumatoid arthritis//Arthritis Rheum. -2000. -Vol. 43. -P. 775-790.
28. Suzuki M., Tetsuka T., Yoshida S., Watanabe N., Kobayashi M., Matsui N., Okamoto T. The role of p38 mitogen-activated protein kinase in IL-6 and IL-8 production from the TNF-alpha-or IL-1beta-stimulated rheumatoid synovial fibroblasts//FEBS Lett. -2000. -Vol. 465. -P. 23-27.
29. Toh M.L., Marotte H., Blond J.L., Jhumka U.,Eljaafari A., Mougin B., Miossec P. Overexpression of synoviolin in peripheral blood and synoviocytes from rheumatoid arthritis patients and continued elevation in nonresponders to infliximab treatment//Arthritis Rheum. -2006. -Vol. 54. -P. 2109-2118.
30. Turner N.A., O'Regan D.J., Ball S.G., Porter K.E. Simvastatin inhibits MMP-9 secretion from human saphenous vein smooth muscle cells by inhibiting the RhoA/ROCK pathway and reducing MMP-9 mRNA levels//FASEB J. -2005. -Vol. 19. -P. 804-806.
31. Yamasaki S., Yagishita N., Tsuchimochi K., Nishioka K., Nakajima T. Rheumatoid arthritis as a hyper-endoplasmic-reticulum-associated degradation disease//Arthritis Res Ther. -2005. -Vol. 7. -P. 181-186.
32. Yano M., Matsumura T., Senokuchi T., Ishii N., Murata Y., Taketa K., Motoshima H., Taguchi T., Sonoda K., Kukidome D., Takuwa Y., Kawada T., Brownlee M., Nishikawa T., Araki E. Statins activate peroxisome proliferator-activated receptor gamma through extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase-dependent cyclooxygenase-2 expression in macrophages//Circ. Res. -2007. -Vol. 100. -P. 1442-1451.
Review
For citations:
Shirinsky I.V., Kozlov V.A., Shirinsky V.S. EFFECTS OF STATINS AND OTHER BIOLOGICAL PREPARATIONS UPON ACTIVATION OF MITOGEN-ACTIVATED PROTEIN KINASES IN PATIENTS WITH RHEUMATOID ARTHRITIS. Medical Immunology (Russia). 2009;11(1):71-78. (In Russ.) https://doi.org/10.15789/1563-0625-2009-1-71-78
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