Distinct Cytokine Profiles in Patients with Oligoarticular Juvenile Idiopathic Arthritis after in Vitro Blockade of Interleukin (IL)-1 and Tumor Necrosis Factor (TNF)-α


Oligoarticular juvenile idiopathic arthritis (oJIA) is an antigen-driven and lymphocyte-mediated autoimmune disorder with irregularity in the adaptive immune system. Auto reactive T cells, activated by cartilage-derived auto antigens, produce pro-inflammatory cytokines as IFN-γ and IL-17. Failure of regulatory T cells leads to decreased anti-inflammatory cytokine IL-10 production and results in the loss of immune tolerance. This activation of innate and adaptive immunity stimulates the release of pro-inflammatory cytokines IL-1, IL-6 and TNF-α. Thus, inhibition of these cytokines is considered as an appropriate therapeutic strategy for oJIA. The aim of this study was to investigate whether the blockade of a single cytokine pathway in the present cytokine setting causes an unfavourable imbalance in the cytokine system or whether the blockade is sufficient to suppress the inflammatory condition. We examined the cytokine secretion after in vitro inhibition of IL-1 and TNF-α of patients with oJIA and healthy subjects. This single center cohort study consisted of oJIA affected children and control subjects. Cytokine profiles from cell culture supernatants were examined with multiplex fluorescent bead immunoassay by flow cytometry. Adalimumab prevents highly effective and very selective effect of the cytokine TNF-α. Due to its structure, the mode of action of etanercept is difficult to display. In addition, adalimumab and etanercept appear in vitro suppressive to IFN-γ. The efficiency of both substances is particularly supported by the increased secretion of anti-inflammatory cytokine IL-4. In contrast, anakinra unselectively inhibits the pro-inflammatory macrophage cytokines. To conclude, our observations suggest that inhibition of IL-1 or TNF-α may contribute to the unselective decline of other pro-inflammatory cytokines in oJIA patients. The selective anti-inflammatory effect of cytokine inhibitors is most likely supported by an increase of IL-4 or IL-10. It still remains to be elucidated whether the reduced IFN-γ secretion is maybe causative for the increased susceptibility to infections with opportunistic pathogens.

Share and Cite:

Kirchner, M. , Strothmann, L. , Sonnenschein, A. and Mannhardt-Laakmann, W. (2014) Distinct Cytokine Profiles in Patients with Oligoarticular Juvenile Idiopathic Arthritis after in Vitro Blockade of Interleukin (IL)-1 and Tumor Necrosis Factor (TNF)-α. World Journal of Vaccines, 4, 110-122. doi: 10.4236/wjv.2014.43014.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Berkun, Y. and Padeh, S. (2010) Environmental Factors and the Geoepidemiology of Juvenile Idiopathic Arthritis. Autoimmunity Reviews, 9, A319-A324.
[2] Kaminiarczyk-Pyzalka, D., Adamczak, K., Mikos, H., Klimecka, I., Moczko, J. and Niedziela, M. (2014) Serum TNF-Alpha Levels and Indicators of Disease Activity in Children with Oligoarticular Juvenile Idiopathic Arthritis (oJIA) in the First Year of the Disease. Clinical Laboratory, 60, 799-807.
[3] Muzaffer, M.A., et al. (2002) Differences in the Profiles of Circulating Levels of Soluble Tumor Necrosis Factor Receptors and Interleukin 1 Receptor Antagonist Reflect the Heterogeneity of the Subgroups of Juvenile Rheumatoid Arthritis. The Journal of Rheumatology, 29, 1071-1078.
[4] Woo, P. (2002) Cytokines and Juvenile Idiopathic Arthritis. Current Rheumatology Reports, 4, 452-457.
[5] Beukelman, T., Patkar, N.M., Saag, K.G., Tolleson-Rinehart, S., Cron, R.Q., De Witt, E.M., et al. (2011) American College of Rheumatology Recommendations for the Treatment of Juvenile Idiopathic Arthritis: Initiation and Safety Monitoring of Therapeutic Agents for the Treatment of Arthritis and Systemic Features. Arthritis Care & Research, 63, 465-482.
[6] Mattey, D.L., Packham, J.C., Nixon, N.B., Coates, L., Creamer, P., Hailwood, S., et al. (2012) Association of Cytokine and Matrix Metalloproteinase Profiles with Disease Activity and Function in Ankylosing Spondylitis. Arthritis Research & Therapy, 14, R127.
[7] Prakken, B.J., Roord, S., Ronaghy, A., Wauben, M., Albani, S. and van Eden, W. (2003) Heat Shock Protein 60 and Adjuvant Arthritis: A Model for T Cell Regulation in Human Arthritis. Springer Seminars in Immunopathology, 25, 47-63.
[8] Gerss, J., Roth, J., Holzinger, D., Ruperto, N., Wittkowski, H., Frosch, M., Wulffraat, N., et al. (2012) Phagocyte-Specific S100 Proteins and High-Sensitivity C Reactive Protein as Biomarkers for a Risk-Adapted Treatment to Maintain Remission in Juvenile Idiopathic Arthritis: A Comparative Study. Annals of the Rheumatic Diseases, 71, 1991-1997.
[9] Holzinger, D., Frosch, M., Kastrup, A., Prince, F.H.M., Otten, M.H., et al. (2012) The Toll-Like Receptor 4 Agonist MRP8/14 Protein Complex Is a Sensitive Indicator for Disease Activity and Predicts Relapses in Systemic-Onset Juvenile Idiopathic Arthritis. Annals of the Rheumatic Diseases, 71, 974-980.
[10] Scardapane, A., Breda, L., Lucantoni, M. and Chiarelli, F. (2012) TNF-Alpha Polymorphisms in Juvenile Idiopathic Arthritis: Which Potential Clinical Implications? International Journal of Rheumatology, 2012, 756291.
[11] Ravelli, A. and Martini, A. (2007) Juvenile Idiopathic Arthritis. Lancet, 369, 767-778.
[12] Zeggini, E., Thomson, W., Kwiatkowski, D., Richardson, A., Ollier, W., Donn, R., et al. (2002) Linkage and Association Studies of Single-Nucleotide Polymorphism-Tagged Tumor Necrosis Factor Haplotypes in Juvenile Oligoarthritis. Arthritis and Rheumatism, 46, 3304-3311.
[13] Schmeling, H., Wagner, U., Peterson, A. and Horneff, G. (2006) Tumor Necrosis Factor Alpha Promoter Polymorphisms in Patients with Juvenile Idiopathic Arthritis. Clinical and Experimental Rheumatology, 24, 103-108.
[14] Mourao, A.F., et al. (2009) Tumor Necrosis Factor-Alpha-308 Genotypes Influence Inflammatory Activity and TNF- Alpha Serum Concentrations in Children with Juvenile Idiopathic Arthritis. The Journal of Rheumatology, 36, 837- 842.
[15] Jimenez-Morales, S., Velázquez-Cruz, R., Ramírez-Bello, J., Bonilla-Gonzálezb, E., Romero-Hidalgoc, S., et al. (2009) Tumor Necrosis Factor-Alpha Is a Common Genetic Risk Factor for Asthma, Juvenile Rheumatoid Arthritis, and Systemic Lupus Erythematosus in a Mexican Pediatric Population. Human Immunology, 70, 251-256.
[16] Modesto, C., Patino-García, A., Sotillo-Pineiro, E., Merino, J., García-Consuegra, J., Merino, R., Rua, M.J., Sierrasesúmaga, L. and Arnal, C. (2005) TNF-α Promoter Gene Polymorphisms in Spanish Children with Persistent Oligoarticular and Systemic-Onset Juvenile Idiopathic Arthritis. Scandinavian Journal of Rheumatology, 34, 451-454.
[17] Schmeling, H. and Horneff, G. (2007) Tumour Necrosis Factor Alpha Promoter Polymorphisms and Etanercept Therapy in Juvenile Idiopathic Arthritis. Rheumatology International, 27, 383-386.
[18] Huizinga, T.W., Westendorp, R.G.J., Bollen, E.L.E.M., Keijsers, V., Brinkman, B.M.N., Langermans, J.A.M., et al. (1997) TNF-α Promoter Polymorphisms, Production and Susceptibility to Multiple Sclerosis in Different Groups of Patients. Journal of Neuroimmunology, 72, 149-153.
[19] Hohler, T., Kruger, A., Schneider, P.M., Schopf, R.E., Knop, J., Rittner, C., zum Büschenfelde, K.H.M. and Marker- Hermann, E. (1997) A TNF-α Promoter Polymorphism Is Associated with Juvenile Onset Psoriasis and Psoriatic Arthritis. The Journal of Investigative Dermatology, 109, 562-565.
[20] Havemose-Poulsen, A., Sorensen, L.K., Stoltze, K., Bendtzen, K. and Holmstrup, P. (2005) Cytokine Profiles in Peripheral Blood and Whole Blood Cell Cultures Associated with Aggressive Periodontitis, Juvenile Idiopathic Arthritis, and Rheumatoid Arthritis. Journal of Periodontology, 76, 2276-2285.
[21] Ruth, N.M. and Passo, M.H. (2012) Juvenile Idiopathic Arthritis: Management and Therapeutic Options. Therapeutic Advances in Musculoskeletal Disease, 4, 99-110.
[22] Lee, J.H., Slifman, N.R., Gershon, S.K., Edwards, E.T., Schwieterman, W.D., Siegel, J.N., Wise, R.P., Lori Brown, S., Udall Jr., J.N. and Miles Braun, M. (2002) Life-Threatening Histoplasmosis Complicating Immunotherapy with Tumor Necrosis Factor α Antagonists Infliximab and Etanercept. Arthritis and Rheumatism, 46, 2565-2570.
[23] Kalliolias, G.D. and Liossis, S.N. (2008) The Future of the IL-1 Receptor Antagonist Anakinra: From Rheumatoid Arthritis to Adult-Onset Still’s Disease and Systemic-Onset Juvenile Idiopathic Arthritis. Expert Opinion on Investigational Drugs, 17, 349-359.
[24] Furst, D.E., Breedveld, F.C., Kalden, J.R., Smolen, J.S., Burmester, G.R., Sieper, J., Emery, P., et al. (2007) Updated Consensus Statement on Biological Agents for the Treatment of Rheumatic Diseases, 2007. Annals of the Rheumatic Diseases, 66, iii2-iii22.
[25] Horneff, G. (2006) Biologics for Treatment of Juvenile Idiopathic Arthritis. Consensus Statement of the 7th Worlitzer Expertengesprache 2004 for the German Arbeitsgemeinschaft Kinderund Jugendrheumatologie. Zeitschrift fur Rheumatologie, 65, 152-156, 158.
[26] Sharma, R., Sharma, C.L. and Mahajan, A. (2008) Biological Agents Targeting beyond TNF-Alpha. Indian Journal of Critical Care Medicine: Peer-Reviewed, Official Publication of Indian Society of Critical Care Medicine, 12, 181-189.
[27] Greenberg, J.D., Reed, G., Kremer, J.M., Tindall, E., Kavanaugh, A., Zheng, C., Bishai, W. and Hochberg, M.C. (2010) Association of Methotrexate and Tumour Necrosis Factor Antagonists with Risk of Infectious Outcomes Including Opportunistic Infections in the CORRONA Registry. Annals of the Rheumatic Diseases, 69, 380-386.
[28] Smith, J.A. and Kauffman, C.A. (2009) Endemic Fungal Infections in Patients Receiving Tumour Necrosis Factor-α Inhibitor Therapy. Drugs, 69, 1403-1415.
[29] Jackson, J.M. (2007) TNF-α Inhibitors. Dermatologic Therapy, 20, 251-264.
[30] Hess, S., Hospach, T., Nossal, R., Dannecker, G., Magdorf, K. and Uhlemann, F. (2011) Life-Threatening Disseminated Tuberculosis as a Complication of TNF-α Blockade in an Adolescent. European Journal of Pediatrics, 170, 1337-1342.
[31] Grainger, R. and Harrison, A. (2005) TNF Inhibitors for Inflammatory Arthritis in New Zealand. The New Zealand Medical Journal, 118, U1706.
[32] Fleischmann, R., Iqbal, I., Nandeshwar, P. and Quiceno, A. (2002) Safety and Efficacy of Disease-Modifying Anti-Rheumatic Agents: Focus on the Benefits and Risks of Etanercept. Drug Safety: An International Journal of Medical Toxicology and Drug Experience, 25, 173-197.
[33] Adib, N., Silman, A. and Thomson, W. (2005) Outcome Following Onset of Juvenile Idiopathic Inflammatory Arthritis: I. Frequency of Different Outcomes. Rheumatology, 44, 995-1001.
[34] Diak, P., Siegel, J., La Grenade, L., Choi, L., Lemery, S. and McMahon, A. (2010) Tumor Necrosis Factor α Blockers and Malignancy in Children: Forty-Eight Cases Reported to the Food and Drug Administration. Arthritis & Rheumatism, 62, 2517-2524.
[35] Hashkes, P.J., Uziel, Y. and Laxer, R.M. (2010) The Safety Profile of Biologic Therapies for Juvenile Idiopathic Arthritis. Nature Reviews. Rheumatology, 6, 561-571.
[36] Horneff, G., Foeldvari, I., Minden, K., Moebius, D. and Hospach, T. (2011) Report on Malignancies in the German Juvenile Idiopathic Arthritis Registry. Rheumatology, 50, 230-236.
[37] Tapping, R.I. (2009) Innate Immune Sensing and Activation of Cell Surface Toll-Like Receptors. Seminars in Immunology, 21, 175-184.
[38] Yao, T.C., Kuo, M.L., See, L.C., Ou, L.S., Lee, W.I., Chan, C.K. and Huang, J.L. (2006) RANTES and Monocyte Chemoattractant Protein 1 as Sensitive Markers of Disease Activity in Patients with Juvenile Rheumatoid Arthritis: A Six-Year Longitudinal Study. Arthritis and Rheumatism, 54, 2585-2593.
[39] Murphy, C.A., Langrish, C.L., Chen, Y., Blumenschein, W., McClanahan, T., Kastelein, R.A., Sedgwick, J.D. and Cua, D.J. (2003) Divergent Pro-and Antiinflammatory Roles for IL-23 and IL-12 in Joint Autoimmune Inflammation. The Journal of Experimental Medicine, 198, 1951-1957.
[40] Roach, D.R., Bean, A.G.D., Demangel, C., France, M.P., Briscoe, H. and Britton, W.J. (2002) TNF Regulates Chemokine Induction Essential for Cell Recruitment, Granuloma Formation, and Clearance of Mycobacterial Infection. Journal of Immunology, 168, 4620-4627.
[41] Toussi, S.S., Pan, N., Walters, H.M. and Walsh, T.J. (2013) Infections in Children and Adolescents with Juvenile Idiopathic Arthritis and Inflammatory Bowel Disease Treated with Tumor Necrosis Factor-α Inhibitors: Systematic Review of the Literature. Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America, 57, 1318-1330.
[42] McAleer, J.P. and Vella, A.T. (2010) Educating CD4 T Cells with Vaccine Adjuvants: Lessons from Lipopolysaccharide. Trends in Immunology, 31, 429-435.
[43] Tamura, T., Yanai, H., Savitsky, D. and Taniguchi, T. (2008) The IRF Family Transcription Factors in Immunity and Oncogenesis. Annual Review of Immunology, 26, 535-584.
[44] Kirchner, M., Sonnenschein, A., Schoofs, S., Schmidtke, P., Umlauf, V.N. and Mannhardt-Laakmann, W. (2013) Surface Expression and Genotypes of Toll-Like Receptors 2 and 4 in Patients with Juvenile Idiopathic Arthritis and Systemic Lupus Erythematosus. Pediatric Rheumatology, 11, 9.
[45] de Jager, W., Hoppenreijs, E.P.A.H., Wulffraat, N.M., Wedderburn, L.R., Kuis, W. and Prakken, B.J. (2007) Blood and Synovial Fluid Cytokine Signatures in Patients with Juvenile Idiopathic Arthritis: A Cross-Sectional Study. Annals of the Rheumatic Diseases, 66, 589-598.
[46] Yilmaz, M., Kendirli, S.G., Altintas, D., Bingol, G. and Antmen, B. (2001) Cytokine Levels in Serum of Patients with Juvenile Rheumatoid Arthritis. Clinical Rheumatology, 20, 30-35.
[47] Lotito, A.P., Campa, A., Silva, C.A., Kiss, M.H. and Mello, S.B. (2007) Interleukin 18 as a Marker of Disease Activity and Severity in Patients with Juvenile Idiopathic Arthritis. The Journal of Rheumatology, 34, 823-830.
[48] Wedderburn, L.R., Robinson, N., Patel, A., Varsani, H. and Woo, P. (2000) Selective Recruitment of Polarized T Cells Expressing CCR5 and CXCR3 to the Inflamed Joints of Children with Juvenile Idiopathic Arthritis. Arthritis and Rheumatism, 43, 765-774.
[49] Gattorno, M., Prigione, I., Morandi, F., Gregorio, A., Chiesa, S., Ferlito, F., et al. (2005) Phenotypic and Functional Characterisation of CCR7+ and CCR7- CD4+ Memory T Cells Homing to the Joints in Juvenile Idiopathic Arthritis. Arthritis Research & Therapy, 7, R256-R267.
[50] Agarwal, S., Misra, R. and Aggarwal, A. (2008) Interleukin 17 Levels Are Increased in Juvenile Idiopathic Arthritis Synovial Fluid and Induce Synovial Fibroblasts to Produce Proinflammatory Cytokines and Matrix Metalloproteinases. The Journal of Rheumatology, 35, 515-519.
[51] Mohler, K.M., Torrance, D.S., Smith, C.A., Goodwin, R.G., Stremler, K.E., Fung, V.P., Madani, H. and Widmer, M.B. (1993) Soluble Tumor Necrosis Factor (TNF) Receptors Are Effective Therapeutic Agents in Lethal Endotoxemia and Function Simultaneously as both TNF Carriers and TNF Antagonists. Journal of Immunology, 151, 1548-1561.
[52] Martin-Mola, E. and Balsa, A. (2009) Infectious Complications of Biologic Agents. Rheumatic Disease Clinics of North America, 35, 183-199.
[53] Favalli, E.G., Desiati, F., Atzeni, F., Sarzi-Puttini, P., Caporali, R., Pallavicini, F.B., Gorla, R., Filippini, M. and Marchesoni, A. (2009) Serious Infections during Anti-TNFα Treatment in Rheumatoid Arthritis Patients. Autoimmunity Reviews, 8, 266-273.
[54] Strangfeld, A., Listing, J., Herzer, P., Liebhaber, A., Rockwitz, K., Richter, C. and Zink, A. (2009) Risk of Herpes Zoster in Patients with Rheumatoid Arthritis Treated with Anti-TNFα Agents. JAMA: The Journal of the American Medical Association, 301, 737-744.
[55] Mori, M., Takei, S., Imagawa, T., Imanaka, H., Nerome, Y., Higuchi, R., et al. (2012) Safety and Efficacy of Long-Term Etanercept in the Treatment of Methotrexate-Refractory Polyarticular-Course Juvenile Idiopathic Arthritis in Japan. Modern Rheumatology/the Japan Rheumatism Association, 22, 720-726.
[56] Bracaglia, C., Buonuomo, P.S., Tozzi, A.E., Pardeo, M., Nicolai, R., Campana, A., Insalaco, A., Cortis, E. and de Benedetti, F. (2012) Safety and Efficacy of Etanercept in a Cohort of Patients with Juvenile Idiopathic Arthritis under 4 Years of Age. The Journal of Rheumatology, 39, 1287-1290.
[57] Tzaribachev, N., Kuemmerle-Deschner, J., Eichner, M. and Horneff, G. (2008) Safety and Efficacy of Etanercept in Children with Juvenile Idiopathic Arthritis below the Age of 4 Years. Rheumatology International, 28, 1031-1034.

Copyright © 2022 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.