Abstract
The purpose of this study was to analyze the effect of the soluble TNF-α receptor etanercept on the serum levels of IL-16, IL-17, IL-23, and macrophage inflammatory protein-3α (MIP-3α) in rheumatoid arthritis (RA) patients. Twenty-two patients with RA were administered etanercept once or twice a week for more than 6 months, and we evaluated clinical and laboratory parameters and serum levels of IL-16, IL-17, IL-23, and MIP-3α at the baseline and at 3 and 6 months. Additionally, the production of IL-23 and MIP-3α of cultured synovial cells stimulated with TNF-α from RA patients was determined by ELISA. We also used ELISA kits to determine synovial fluid (SF) levels of IL-17, IL-23, and MIP-3α in patients with RA, osteoarthritis (OA), pseudogouty arthritis (PGA), and gouty arthritis (GA). A significant decrease in serum levels of IL-23 and MIP-3α was observed at 3 and 6 months after initial treatment of etanercept. TNF-α induced MIP-3α but not IL-23 production in cultured synovial cells from RA patients. SF levels of IL-17, IL-23, and MIP-3α in RA patients showed significantly higher levels than those of OA, PGA, and GA patients. This study demonstrated that the reduction of IL-23 and MIP-3α production in RA patients was a newly determined function of etanercept
Similar content being viewed by others
References
Arend WP, Dayer J-M (1995) Inhibition of the production and effects of interleukin-1 and tumor necrosis factor alpha in rheumatoid arthritis. Arthritis Rheum 38:151–160
Maini RN, Taylor PC (2000) Anti-cytokine therapy for rheumatoid arthritis. Annu Rev Med 51:207–229
Woo CH, Kim TH, Choi JA, Ryu HC, Lee JE, You HJ, Bae YS, Kim JH (2006) Inhibition of receptor internalization attenuates the TNF alpha-induced ROS generation in non-phagocytic cells. Biochem Biophys Res Commun 351:972–978
Sakon S, Xue X, Takekawa M, Sasazuki T, Okazaki T, Kojima Y, Piao JH, Yagita H, Okumura K, Doi T, Nakano H (2003) NF-kappa B inhibits TNF-induced accumulation of ROS that mediate prolonged MAPK activation and necrotic cell death. EMBO J 22:3898–3909
Paleolog EM, Young S, Stark AC, McCloskey RV, Feldmann M, Maini RN (1998) Modulation of angiogenic vascular endothelial growth factor by tumor necrosis factor alpha and interleukin-1 in rheumatoid arthritis. Arthritis Rheum 41:1258–1265
Feldmann M, Maini RN (2001) Anti-TNF alpha therapy of rheumatoid arthritis: what have we learned? Annu Rev Immunol 19:163–196
Pittoni V, Bombardieri M, Spinelli FR, Scrivo R, Alessandri C, Conti F, Spadaro A, Valesini G (2002) Anti-tumour necrosis factor (TNF) alpha treatment of rheumatoid arthritis (infliximab) selectively down regulates the production of interleukin (IL) 18 but not of IL12 and IL13. Ann Rheum Dis 61:723–725
Klimiuk PA, Sierakowski S, Domyslawska I, Chwiecko J (2004) Effect of repeated infliximab therapy on serum matrix metalloproteinases and tissue inhibitors of metalloproteinases in patients with rheumatoid arthritis. J Rheumatol 31:238–242
Kageyama Y, Takahashi M, Torikai E, Suzuki M, Ichikawa T, Nagafusa T, Koide Y, Nagano A (2007) Treatment with anti-TNF-alpha antibody infliximab reduces serum IL-15 levels in patients with rheumatoid arthritis. Clin Rheumatol 26:505–509
Torikai E, Kageyama Y, Suzuki M, Ichikawa T, Nagano A (2007) The effect of infliximab on chemokines in patients with rheumatoid arthritis. Clin Rheumatol 26:1088–1093
Kinne RW, Brauer R, Stuhlmuller B, Palombo-Kinne E, Burmester GR (2000) Macrophages in rheumatoid arthritis. Arthritis Res 2:189–202
Szekanecz Z, Kim J, Koch AE (2003) Chemokines and chemokine receptors in rheumatoid arthritis. Semin Immunol 15:15–21
Dieu-Nosjean MC, Massacrier C, Homey B, Vanbervliet B, Pin JJ, Vicari A, Lebecque S, Dezutter-Dambuyant C, Schmitt D, Zlotnik A, Caux C (2000) Macrophage inflammatory protein 3 alpha is expressed at inflamed epithelial surfaces and is the most potent chemokine known in attracting Langerhans cell precursors. J Exp Med 192:705–718
Kleeff J, Kusama T, Rossi DL, Ishiwata T, Maruyama H, Friess H, Buchler MW, Zlotnik A, Korc M (1999) Detection and localization of Mip-3alpha/LARC/Exodus, a macrophage proinflammatory chemokine, and its CCR6 receptor in human pancreatic cancer. Int J Cancer 81:650–657
Schutyser E, Struyf S, Menten P, Lenaerts JP, Conings R, Put W, Wuyts A, Proost P, Van Damme J (2000) Regulated production and molecular diversity of human liver and activation-regulated chemokine/macrophage inflammatory protein-3 alpha from normal and transformed cells. J Immunol 165:4470–4477
Chabaud M, Page G, Miossec P (2001) Enhancing effect of IL-1, IL-17, and TNF-alpha on macrophage inflammatory protein-3 alpha production in rheumatoid arthritis: regulation by soluble receptors and Th2 cytokines. J Immunol 167:6015–6020
Murphy CA, Langrish CL, Chen Y, Blumenschein W, McClanahan T, Kastelein RA, Sedgwick JD, Cua DJ (2003) Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J Exp Med 198:1951–1957
Gottlieb AB, Chamian F, Masud S, Cardinale I, Abello MV, Lowes MA, Chen F, Magliocco M, Krueger JG (2005) TNF inhibition rapidly down-regulates multiple proinflammatory pathways in psoriasis plaques. J Immunol 175:2721–2729
Cho ML, Kang JW, Moon YM, Nam HJ, Jhun JY, Heo SB, Jin HT, Min SY, Ju JH, Park KS, Cho YG, Yoon CH, Park SH, Sung YC, Kim HY (2006) STAT3 and NF-B signal pathway is required for IL-23-mediated IL-17 production in spontaneous arthritis animal model IL-1 receptor antagonist-deficient mice. J Immunol 176:5652–5661
Hoeve MA, Savage ND, de Boer T, Langenberg DM, de Waal Malefyt R, Ottenhoff TH, Verreck FA (2006) Divergent effects of IL-12 and IL-23 on the production of IL-17 by human T cells. Eur J Immunol 36:661–670
Glabinski AR, Bielecki B, Kawczak JA, Tuohy VK, Selmaj K, Ransohoff RM (2004) Treatment with soluble tumor necrosis factor receptor (sTNFR):Fc/p80 fusion protein ameliorates relapsing-remitting experimental autoimmune encephalomyelitis and decreases chemokine expression. Autoimmunity 37:465–471
Madhusudan S, Foster M, Muthuramalingam SR, Braybrooke JP, Wilner S, Kaur K, Han C, Hoare S, Balkwill F, Talbot DC, Ganesan TS, Harris AL (2004) A phase II study of etanercept (Enbrel), a tumor necrosis factor alpha inhibitor in patients with metastatic breast cancer. Clin Cancer Res 10:6528–6534
Catrina AI, Lampa J, Ernestam S, af Klint E, Bratt J, Klareskog L, Ulfgren AK (2002) Anti-tumour necrosis factor (TNF)-alpha therapy (etanercept) down-regulates serum matrix metalloproteinase (MMP)-3 and MMP-1 in rheumatoid arthritis. Rheumatology (Oxford) 41:484–489
Kikly K, Liu L, Na S, Sedgwick JD (2006) The IL-23/Th(17) axis: therapeutic targets for autoimmune inflammation. Curr Opin Immunol 18:670–675
Chen Y, Langrish CL, McKenzie B, Joyce-Shaikh B, Stumhofer JS, McClanahan T, Blumenschein W, Churakovsa T, Low J, Presta L, Hunter CA, Kastelein RA, Cua DJ (2006) Anti-IL-23 therapy inhibits multiple inflammatory pathways and ameliorates autoimmune encephalomyelitis. J Clin Invest 116:1317–1326
Cua DJ, Sherlock J, Chen Y, Murphy CA, Joyce B, Seymour B, Lucian L, To W, Kwan S, Churakova T, Zurawski S, Wiekowski M, Lira SA, Gorman D, Kastelein RA, Sedgwick JD (2003) Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421:744–748
Kotake S, Udagawa N, Takahashi N, Matsuzaki K, Itoh K, Ishiyama S, Saito S, Inoue K, Kamatani N, Gillespie MT, Martin TJ, Suda T (1999) IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J Clin Invest 103:1345–1352
Chabaud M, Durand JM, Buchs N, Fossiez F, Page G, Frappart L, Miossec P (1999) Human interleukin-17: a T cell-derived proinflammatory cytokine produced by the rheumatoid synovium. Arthritis Rheum 42:963–970
Ziolkowska M, Koc A, Luszczykiewicz G, Ksiezopolska-Pietrzak K, Klimczak E, Chwalinska-Sadowska H, Maslinski W (2000) High levels of IL-17 in rheumatoid arthritis patients: IL-15 triggers in vitro IL-17 production via cyclosporin A-sensitive mechanism. J Immunol 164:2832–2838
Happel KI, Zheng M, Young E, Quinton LJ, Lockhart E, Ramsay AJ, Shellito JE, Schurr JR, Bagby GJ, Nelson S, Kolls JK (2003) Cutting edge: roles of Toll-like receptor 4 and IL-23 in IL-17 expression in response to Klebsiella pneumoniae infection. J Immunol 170:4432–4436
Sheibanie AF, Tadmori I, Jing H, Vassiliou E, Ganea D (2004) Prostaglandin E2 induces IL-23 production in bone marrow-derived dendritic cells. FASEB J 18:1318–1320
Lee HJ, Choi SC, Lee MH, Oh HM, Choi EY, Choi EJ, Yun KJ, Seo GS, Kim SW, Lee JG, Han WC, Park KI, Jun CD (2005) Increased expression of MIP-3alpha/CCL20 in peripheral blood mononuclear cells from patients with ulcerative colitis and its down-regulation by sulfasalazine and glucocorticoid treatment. Inflamm Bowel Dis 11:1070–1079
Baba M, Imai T, Nishimura M, Kakizaki M, Takagi S, Hieshima K, Nomiyama H, Yoshie O (1997) Identification of CCR6, the specific receptor for a novel lymphocyte-directed CC chemokine LARC. J Biol Chem 272:14893–14898
Power CA, Church DJ, Meyer A, Alouani S, Proudfoot AE, Clark-Lewis I, Sozzani S, Mantovani A, Wells TN (1997) Cloning and characterization of a specific receptor for the novel CC chemokine MIP-3alpha from lung dendritic cells. J Exp Med 186:825–835
Akahoshi T, Sasahara T, Namai R, Matsui T, Watabe H, Kitasato H, Inoue M, Kondo H (2003) Production of macrophage inflammatory protein 3 alpha (MIP-3alpha) (CCL20) and MIP-3beta (CCL19) by human peripheral blood neutrophils in response to microbial pathogens. Infect Immun 71:524–526
Vanbervliet B, Homey B, Durand I, Massacrier C, Ait-Yahia S, de Bouteiller O, Vicari A, Caux C (2002) Sequential involvement of CCR2 and CCR6 ligands for immature dendritic cell recruitment: possible role at inflamed epithelial surfaces. Eur J Immunol 32:231–242
Greaves DR, Wang W, Dairaghi DJ, Dieu MC, Saint-Vis B, Franz-Bacon K, Rossi D, Caux C, McClanahan T, Gordon S, Zlotnik A, Schall TJ (1997) CCR6, a CC chemokine receptor that interacts with macrophage inflammatory protein 3 alpha and is highly expressed in human dendritic cells. J Exp Med 186:837–844
Matsui T, Akahoshi T, Namai R, Hashimoto A, Kurihara Y, Rana M, Nishimura A, Endo H, Kitasato H, Kawai S, Takagishi K, Kondo H (2001) Selective recruitment of CCR6-expressing cells by increased production of MIP-3 alpha in rheumatoid arthritis. Clin Exp Immunol 125:155–161
Szekanecz Z, Strieter RM, Kunkel SL, Koch AE (1998) Chemokines in rheumatoid arthritis. Springer Semin Immunopathol 20:115–132
Chevrel G, Garnero P, Miossec P (2002) Addition of interleukin-1 (IL1) and IL17 soluble receptors to a tumour necrosis factor soluble receptor more effectively reduces the production of IL6 and macrophage inhibitory protein-3 and increases that of collagen in an in vitro model of rheumatoid synoviocyte activation. Ann Rheum Dis 61:730–733
Sugita S, Kohno T, Yamamoto K, Imaizumi Y, Nakajima H, Ishimaru T, Matsuyama T (2002) Induction of macrophage-inflammatory protein-3 alpha gene expression by TNF-dependent NF-kappaB activation. J Immunol 168:5621–5628
Lisignoli G, Piacentini A, Cristino S, Grassi F, Cavallo C, Cattini L, Tonnarelli B, Manferdini C, Facchini A (2007) CCL20 chemokine induces both osteoblast proliferation and osteoclast differentiation: Increased levels of CCL20 are expressed in subchondral bone tissue of rheumatoid arthritis patients. J Cell Physiol 210:798–806
Franz JK, Kolb SA, Hummel KM, Lahrtz F, Neidhart M, Aicher WK, Pap T, Gay RE, Fontana A, Gay S (1998) Interleukin-16, produced by synovial fibroblasts, mediates chemoattraction for CD4+ T lymphocytes in rheumatoid arthritis. Eur J Immunol 28:2661–2671
Klimiuk PA, Goronzy JJ, Weyand CM (1999) IL-16 as an anti-inflammatory cytokine in rheumatoid synovitis. J Immunol 162:4293–4299
Atkins GJ, Haynes DR, Geary SM, Loric M, Crotti TN, Findlay DM (2000) Coordinated cytokine expression by stromal and hematopoietic cells during human osteoclast formation. Bone 26:653–661
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kageyama, Y., Ichikawa, T., Nagafusa, T. et al. Etanercept reduces the serum levels of interleukin-23 and macrophage inflammatory protein-3 alpha in patients with rheumatoid arthritis. Rheumatol Int 28, 137–143 (2007). https://doi.org/10.1007/s00296-007-0388-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00296-007-0388-4