CYTOKINE LEVELS IN PATIENTS WITH RHEUMATOID ARTHRITIS: AN ASSOCIATION WITH LUNG INJURY

The basis for the pathogenesis of rheumatoid arthritis (RA) is an imbalance in the production of proinflammatory and anti-inflammatory cytokines, which may favor the development of systemic manifestations, interstitial lung injury (ILI) in particular.

Objective: to study cytokine concentrations in RA patients with and without ILI.

Subjects and methods. The investigation enrolled three groups. Group 1 included 20 RA patients with ILI; Group 2 comprised 30 RA patients without ILI and Group 3 consisted of 28 healthy donors. All the RA inpatients were treated at the V.A. Nasonova Research Institute of Rheumatology. The diagnosis of RA was made on the basis of the 1987
American College of Rheumatology (ACR) criteria. The serum concentrations of 27 cytokines were determined utilizing multiplex xMAP technology with a Bio-Plex200 analyzer (Bio-Rad, USA). Lung computed tomography (CT) with a GE Light Speed VCT spiral CT scanner (with a section thickness of 0.65 mm) was carried out to detect ILI.

Results. As compared with the healthy donors, the RA patients with and without ILI were observed to have significantly elevated concentrations of interleukin 5 (IL-5), IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-15, eotaxin, granulocyte colony-stimulating factor, granulocyte macrophage colony-stimulating factor, interferon-γ (IFN-γ), macrophage inflammatory protein-1β, platelet-derived growth factor BB, RANTES, and tumor necrosis factor-α. In the RA patients with ILI, the concentrations of IL-4 and IFN-γ-inducible protein proved to be higher than in the other
groups; however, these differences reached statistical significance compared to only the healthy donors (p = 0.04 and p = 0.001, respectively). The RA patients with ILI were found to have a significant increase in IL-10 and IFN-γ levels as compared to those without ILI and the healthy donors (p = 0.008 and p = 0.0003; p = 0.0001 and p = 0.0001, respectively). Vascular endothelial growth factor concentrations were found to be lower in the RA patients with ILI than in the healthy donors (p = 0.05).

Conclusion. The RA patients with ILI show a predominance of a Th2 immune response. The found activation of humoral antigen-specific immune response regulators, such as IL-4, IL-5, IL-6, IL-10, and IFN-γ, substantiates the use of anti-B-cell therapy for this type of the disease.

1. Насонов ЕЛ. Ревматоидный артрит как общемедицинская проблема. Терапевт. 2004;(5):5–7. [Nasonov EL. Rheumatoid arthritis as all-medical problem. Terapevt. 2004;(5):5–7. (In Russ.)]

2. Насонов ЕЛ, Каратеев ДЕ, Балабанова РМ. Ревматоидный артрит. В кн.: Ревматология: Национальное руководство. Под ред. Е.Л. Насонова, В.А. Насоновой. Москва: ГЭОТАР- Медиа; 2008. С. 290–331. [Nasonov EL, Karateev DE, Balabanova RM. Rheumatoid arthritis. In: Revmatologiya. Natsional'noe rukovodstvo [Rheumatology. National Guide]. Nasonov EL, Nasonova VA, editors. Moscow: GEOTAR-media; 2008. P. 290–331.]

3. Насонов ЕЛ, редактор. Ревматология: Клинические рекомендации. Москва: ГЭОТАР-Медиа; 2010. 752 c. [Nasonov EL, editor. Revmatologiya: Klinicheskie rekomendatsii [Rheumatology: Clinical recommendations]. Moscow: GEOTARMedia; 2010. 752 p.]

4. Ройт А, Бростофф Дж, Мейл Д. Иммунология. Москва: Мир; 2000. 230 c. [Royt A, Brostoff Dzh, Meyl D. Immunologiya [Immunology]. Moscow: Mir; 2000. 230 p.]

5. Brennan F, Mclnnes I. Evidence that cytokines play a role in rrheumatoid arthritis. J Clin Invest. 2008;118(11):3537–45. DOI: http://dx.doi.org/10.1172/JCI36389.

6. Kingsmore S. Multiplexed protein measurement:technologies and applications of protein and antibody arrays. Nat Rev Drug Discov. 2006;5(4):310–20. DOI: http://dx.doi.org/10.1038/nrd2006.

7. Новиков АА, Александрова ЕН, Попкова ТВ и др. Роль мультиплексного анализа цитокинов в оценке эффективности ритуксимаба при лечении ревматоидного артрита. Научно-практическая ревматология. 2011;(5):51–7. [Novikov AA, Aleksandrova EN, Popkova TV, et al. Role of multiplex cytokine analysis in the evaluation of the efficacy of rituximab during treatment for rheumatoid arthritis. Nauchno-prakticheskaya revmatologiya = Rheumatology Science and Practice. 2011;(5):51–7. (In Russ.)]. DOI: http://dx.doi.org/10.14412/1995-4484-2011-1461.

8. Carmona L, Gonzalez-Alvaro I, Balsa A, et al. Rheumatoid arthritis in Spain: occurrence of extra-articular manifestations and estimates of disease severity. Ann Rheum Dis. 2003;62(9):897–900. DOI: http://dx.doi.org/10.1136/ard.62.9.897.

9. Bilgici A, Ulusoy H, Kuru O, et al. Pulmonary involvement in rheumatoid arthritis. Rheumatol Int. 2005;25(6):429–35. DOI: http://dx.doi.org/10.1007/s00296-004-0472-y.

10. Lee HK, Kim DS, Yoo B, et al. Histopathologic pattern and clinical features of rheumatoid arthritis-associated interstitial lung disease. Chest. 2005;127(6):2019–27. DOI: http://dx.doi.org/10.1378/chest.127.6.2019.

11. Nannini C, Ryu JH, Matteson EL. Lung disease in rheumatoid arthritis. Curr Opin Rheumatol. 2008;20(3):340–46. DOI: 10.1097/BOR.0b013e3282f798ed.

12. Thannickal VJ, Toews GB, White ES, et al. Mechanisms of pulmonary fibrosis. Annu Rev Med. 2004;(55):395–417. DOI: http://dx.doi.org/10.1146/annurev.med.55.091902.103810.

13. Bringardner BD, Baran CP, Eubank TD, Marsh CB. The role of inflammation in the pathogenesis of idiopathic pulmonary fibrosis. Antioxid Redox Signal. 2008;10(2):287–301. DOI:http://dx.doi.org/10.1089/ars.2007.1897.

14. Thavarajah K, Wu P, Rhew EJ, et al. Pulmonary complications of tumor necrosis factor-targeted therapy. Respir Med. 2009;103(5):661–9. DOI: 10.1016/j.rmed.2009.01.002. Epub 2009 Feb 7.

15. Lappalainen U, Whitsett JA, Wert SE, et al. Interleukin-1beta causes pulmonary inflammation, emphysema, and airway remodeling in the adult murine lung. Am J Respir Cell Mol Biol. 2005;32(4):311–8. DOI: http://dx.doi.org/10.1165/rcmb.2004-0309OC.

16. Ortiz LA, Dutreil M, Fattman C, et al. Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury. Proc Natl Acad Sci USA. 2007;104:11002–7. DOI: http://dx.doi.org/10.1073/pnas.0704421104.

17. Wynn TA. Fibrotic disease and the T(H)1/T(H)2 paradigm. Nat Rev Immunol. 2004;4(8):583–94. DOI:http://dx.doi.org/10.1038/nri1412.

18. Dinarello CA. Interleukin-1 beta, interleukin-18, and the interleukin-1 beta, converting enzyme. Ann NY Acad Sci. 1998;29(856):1–11. DOI: http://dx.doi.org/10.1111/j.1749-6632.1998.tb08307.x.

19. Hom JT, Bendele AM, Carlson DG. In vivo administration with IL-1 accelerates the development of collagen-induced arthritis in mice. J Immunol. 1998;141(3):834–4.

20. Fulkerson PC, Fischetti CA, Rothenberg ME. Eosinophils and CCR3 regulate interleukin-13 transgene-induced pulmonary remodeling. Am J Pathol. 2006;169(6):2117–26. DOI: http://dx.doi.org/10.2353/ajpath.2006.060617.

21. Ramalingam TR, Pesce JT, Sheikh F, et al. Unique functions of the type II interleukin 4 receptor identified in mice lacking the interleukin 13 receptor alpha1 chain. Nat. Immunol. 2008;9:25–33. DOI: http://dx.doi.org/10.1038/ni1544.

22. Lupardus PJ, Birnbaum ME, Garcia KC. Molecular basis for shared cytokine recognition revealed in the structure of an unusually high affinity complex between IL-13 and IL-13Ralpha2. Structure. 2010;18(3):332–42. DOI: 10.1016/j.str.2010.01.003.

23. Wilson MS, Elnekave E, Mentink-Kane M, et al. IL-13Ralpha2 and IL-10 coordinately suppress airway inflammation, airwayhyperreactivity, and fibrosis in mice. J Clin Invest. 2007;117(10):2941–51. DOI:http://dx.doi.org/10.1172/JCI31546.

24. Strieter RM, Belperio JA, Keane MP. CXC chemokines in vascular remodeling related to pulmonary fibrosis. Am J Respir Cell Mol Biol. 2003;29(3 Suppl):S67–9.

25. Simonian PL, Roark CL, Wehrmann F, et al. Th17-polarized immune response in a murine model of hypersensitivity pneumonitis and lung fibrosis. J Immunol. 2009;182(1):657–65. DOI: http://dx.doi.org/10.4049/jimmunol.182.1.657.

26. Wilson MS, Madala SK, Ramalingam TR, et al. Bleomycin and IL-1β-mediated pulmonary fibrosis is IL-17A dependent. J Exp Med. 2010;207(3):535–52. DOI: 10.1084/jem.20092121. Epub 2010 Feb 22.

27. Brodlie M, McKean MC, Johnson GE, et al. Raised interleukin-17 is immunolocalised to neutrophils in cystic fibrosis lung disease. Eur Respir J. 2011;37(6):1378–85. DOI: 10.1183/09031936.00067110. Epub 2010 Nov 25.

28. Hariyawasam HH, Nicholson GC, Tan AJ, et al. Effects of Anti-IL-13 (Novartis QAX576) on Inflammatory Responses Following Nasal Allergen Challenge (NAC). Am J Respir Crit Care Med. 2009;179:A3642.

29. Dayer J, Beutler B, Cerami A. Cachectin/tumor necrosis factor stimulates collagenase and prostaglandin E2 production by human synovial cells and dermal fibroblasts. J Exp Med. 1985;162(6):2163–8. DOI: http://dx.doi.org/10.1084/jem.162.6.2163.

30. Bazzoni E, Beutler B. The tumor necrosis factor ligand and receptor families. N Engl J Med. 1996;334(2):1717–25.