Systemic levels of IL-23 are strongly associated with disease activity in rheumatoid arthritis but not spondyloarthritis

Objectives Th17 cells are an effector T-cell population that plays a role in chronic inflammatory conditions and is dependent on IL-23 for their survival and expansion. More recently, a genetic association was discovered between polymorphisms in the gene coding for the IL-23 receptor and spondyloarthritis. This study aimed to evaluate the role of Th17-associated cytokines in spondyloarthritis pathogenesis by measuring their levels in the joints and circulation as well as correlating them with disease activity parameters. Methods Paired synovial fluid (SF), serum and synovial biopsies were obtained from 30 non-PsA (psoriatic arthritis) spondyloarthritis, 22 PsA and 22 rheumatoid arthritis (RA) patients. IL-17, IL-23 and CCL20 were measured by ELISA in the SF and serum of patients and correlated with systemic and local parameters of disease activity. Results Concentrations of CCL20, a major Th17-attracting chemokine, tended to be higher in the joints of RA than in spondyloarthritis patients. Interestingly, levels of CCL20 were markedly higher in SF as opposed to serum. In addition, there was a remarkable association between the expression of the Th17 cytokine system and the presence of intimal lining layer hyperplasia in RA. Also in the serum, there was a tendency for higher IL-23 levels in RA, which correlated strongly with disease activity parameters. Conclusions Th17-related cytokines are expressed in joints of spondyloarthritis as well as RA patients. IL-23 levels, however, correlate with disease activity parameters in RA only. These results point towards a differential regulation of the Th17 cytokine system in spondyloarthritis compared with RA.

[1]  D. D’Lima,et al.  Rho kinase-dependent CCL20 induced by dynamic compression of human chondrocytes. , 2008, Arthritis and rheumatism.

[2]  S. Chevalier,et al.  Chronically Inflamed Human Tissues Are Infiltrated by Highly Differentiated Th17 Lymphocytes , 2008, The Journal of Immunology.

[3]  L. Wedderburn,et al.  Interleukin-17–producing T cells are enriched in the joints of children with arthritis, but have a reciprocal relationship to regulatory T cell numbers , 2008, Arthritis and rheumatism.

[4]  Lisa C. Zaba,et al.  Amelioration of epidermal hyperplasia by TNF inhibition is associated with reduced Th17 responses , 2007, The Journal of experimental medicine.

[5]  Hiromu Ito,et al.  Preferential recruitment of CCR6-expressing Th17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model , 2007, The Journal of experimental medicine.

[6]  Y. Obata,et al.  A Proximal κB Site in the IL-23 p19 Promoter Is Responsible for RelA- and c-Rel-Dependent Transcription , 2007, The Journal of Immunology.

[7]  Simon C. Potter,et al.  Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants , 2007, Nature Genetics.

[8]  D. Hommes,et al.  Stimulation of the intracellular bacterial sensor NOD2 programs dendritic cells to promote interleukin-17 production in human memory T cells. , 2007, Immunity.

[9]  Kathleen M. Smith,et al.  Development, cytokine profile and function of human interleukin 17–producing helper T cells , 2007, Nature Immunology.

[10]  L. Cosmi,et al.  Phenotypic and functional features of human Th17 cells , 2007, The Journal of experimental medicine.

[11]  A. Nagano,et al.  Etanercept reduces the serum levels of interleukin-23 and macrophage inflammatory protein-3 alpha in patients with rheumatoid arthritis , 2007, Rheumatology International.

[12]  Simon C. Potter,et al.  Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls , 2007, Nature.

[13]  D. Jarrossay,et al.  Surface phenotype and antigenic specificity of human interleukin 17–producing T helper memory cells , 2007, Nature Immunology.

[14]  J. Ruland,et al.  Syk- and CARD9-dependent coupling of innate immunity to the induction of T helper cells that produce interleukin 17 , 2007, Nature Immunology.

[15]  R. Nussenblatt,et al.  TH17 cells contribute to uveitis and scleritis and are expanded by IL-2 and inhibited by IL-27/STAT1 , 2007, Nature Medicine.

[16]  D. Wendling,et al.  Serum IL-17, BMP-7, and bone turnover markers in patients with ankylosing spondylitis. , 2007, Joint, bone, spine : revue du rhumatisme.

[17]  R. D. Hatton,et al.  IL-17 family cytokines and the expanding diversity of effector T cell lineages. , 2007, Annual review of immunology.

[18]  M. Lebwohl,et al.  A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. , 2007, The New England journal of medicine.

[19]  P. Valdez,et al.  Interleukin-22, a TH17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis , 2007, Nature.

[20]  Steven J. Schrodi,et al.  A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. , 2007, American journal of human genetics.

[21]  Judy H. Cho,et al.  A Genome-Wide Association Study Identifies IL23R as an Inflammatory Bowel Disease Gene , 2006, Science.

[22]  Dafna Gladman,et al.  Classification criteria for psoriatic arthritis: development of new criteria from a large international study. , 2006, Arthritis and rheumatism.

[23]  M. Breban Genetics of spondyloarthritis. , 2006, Best practice & research. Clinical rheumatology.

[24]  L. Joosten,et al.  Interleukin-17 Acts Independently of TNF-α under Arthritic Conditions1 , 2006, The Journal of Immunology.

[25]  T. Mcclanahan,et al.  IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. , 2006, The Journal of clinical investigation.

[26]  L. Joosten,et al.  Blocking of interleukin-17 during reactivation of experimental arthritis prevents joint inflammation and bone erosion by decreasing RANKL and interleukin-1. , 2005, The American journal of pathology.

[27]  M. Neurath,et al.  Anti-interleukin-12 antibody for active Crohn's disease. , 2004, The New England journal of medicine.

[28]  D. Baeten,et al.  Involvement of matrix metalloproteinases and their inhibitors in peripheral synovitis and down-regulation by tumor necrosis factor alpha blockade in spondylarthropathy. , 2004, Arthritis and rheumatism.

[29]  T. Mcclanahan,et al.  Divergent Pro- and Antiinflammatory Roles for IL-23 and IL-12 in Joint Autoimmune Inflammation , 2003, The Journal of experimental medicine.

[30]  Pawan Kumar,et al.  Role of Macrophage Inflammatory Protein-3α and Its Ligand CCR6 in Rheumatoid Arthritis , 2003, Laboratory Investigation.

[31]  S. Ferretti,et al.  IL-17, Produced by Lymphocytes and Neutrophils, Is Necessary for Lipopolysaccharide-Induced Airway Neutrophilia: IL-15 as a Possible Trigger , 2003, The Journal of Immunology.

[32]  A. Gurney,et al.  Interleukin-23 Promotes a Distinct CD4 T Cell Activation State Characterized by the Production of Interleukin-17* , 2003, The Journal of Biological Chemistry.

[33]  J. Shellito,et al.  Requirement of Interleukin 17 Receptor Signaling for Lung Cxc Chemokine and Granulocyte Colony-Stimulating Factor Expression, Neutrophil Recruitment, and Host Defense , 2001, The Journal of experimental medicine.

[34]  L. Joosten,et al.  IL-1-Independent Role of IL-17 in Synovial Inflammation and Joint Destruction During Collagen-Induced Arthritis1 , 2001, The Journal of Immunology.

[35]  T. Matsui,et al.  Selective recruitment of CCR6‐expressing cells by increased production of MIP‐3α in rheumatoid arthritis , 2001, Clinical and experimental immunology.

[36]  J Wagner,et al.  Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. , 2000, Immunity.

[37]  A. Foussat,et al.  Regulation of CCR6 chemokine receptor expression and responsiveness to macrophage inflammatory protein-3alpha/CCL20 in human B cells. , 2000, Blood.

[38]  J. Lötvall,et al.  Neutrophil recruitment by human IL-17 via C-X-C chemokine release in the airways. , 1999, Journal of immunology.

[39]  C. Caux,et al.  Selective Recruitment of Immature and Mature Dendritic Cells by Distinct Chemokines Expressed in Different Anatomic Sites , 1998, The Journal of experimental medicine.

[40]  P. Miossec,et al.  Enhancing effect of IL-17 on IL-1-induced IL-6 and leukemia inhibitory factor production by rheumatoid arthritis synoviocytes and its regulation by Th2 cytokines. , 1998, Journal of immunology.

[41]  H. Nomiyama,et al.  Identification of CCR6, the Specific Receptor for a Novel Lymphocyte-directed CC Chemokine LARC* , 1997, The Journal of Biological Chemistry.

[42]  M. Dougados,et al.  The European Spondylarthropathy Study Group preliminary criteria for the classification of spondylarthropathy. , 1991, Arthritis and rheumatism.

[43]  M. Liang,et al.  The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. , 1988, Arthritis and rheumatism.

[44]  D. Goldenberg,et al.  SYNOVIAL MEMBRANE HISTOPATHOLOGY IN THE DIFFERENTIAL DIAGNOSIS OF RHEUMATOID ARTHRITIS, GOUT, PSEUDOGOUT, SYSTEMIC LUPUS ERYTHEMATOSUS, INFECTIOUS ARTHRITIS AND DEGENERATIVE JOINT DISEASE , 1978, Medicine.

[45]  B. Thiers A Large-Scale Genetic Association Study Confirms IL12B and Leads to the Identification of IL23R as Psoriasis-Risk Genes , 2008 .

[46]  C. Eun A Genome-Wide Association Study Identifies IL23R as an Inflammatory Bowel Disease Gene. , 2007 .

[47]  F. Padova,et al.  Interleukin-17 Acts Independently of TNF- , 2006 .

[48]  D. Elewaut,et al.  Needle Arthroscopy of the Knee with Synovial Biopsy Sampling: Technical Experience in 150 Patients , 1999, Clinical Rheumatology.