A POSSIBLE ROLE FOR SOLUBLE IL-6 RECEPTOR IN THE PATHOGENESIS OF SYSTEMIC ONSET JUVENILE CHRONIC ARTHRITIS

doi:10.1006/cyto.1997.0343

Cytokine

Volume 10, Issue 9, September 1998, Pages 729-734

https://doi.org/10.1006/cyto.1997.0343 Get rights and content

Abstract

Investigation of the agonist and two antagonists to interleukin 6 (IL-6) and their possible role in the pathogenesis of different sub-groups of juvenile chronic arthritis (JCA). Sera of 54 patients and 10 age-matched controls were tested: 20 with pauci-articular JCA, 12 with polyarticular JCA, and 22 systemic JCA. Interleukin 6, soluble interleukin 6 receptor (agonist), soluble gp130 and autoantibodies to IL-6 (antagonist to IL-6) were measured, as well as C-reactive protein as an indicator of disease activity. In addition, during fever two systemic JCA patients were analysed longitudinally for these parameters. There was a significant increase in soluble IL-6 receptor (sIL-6R) concentrations. No difference in the levels of soluble gp130 and autoantibodies to IL-6 in the systemic JCA group was found. In two patients the fever curves corresponded to the IL-6 levels measured. sIL-6R serum concentrations also showed a tendency to follow the fever. The authors have shown that in systemic JCA, the levels of sIL-6R, agonist of IL-6, were increased significantly compared to the other groups, while levels of antagonists to IL-6 were not changed in the face of increased levels of IL-6 in systemic JCA. These results suggest an imbalance of IL-6 homeostasis.

References (0)

Cited by (73)

Polymorphisms in IL-2 and IL-6R increase serum levels of the respective interleukins in differentiated thyroid cancer
2020, Meta Gene
To investigate polymorphisms of IL-2 and IL-6R genes in patients with differentiated thyroid cancer (DTC), correlating them to previously obtained data on serum levels of IL-2 and IL-6R with DTC.
We evaluated the polymorphic inheritance of 300 malignant thyroid nodule patients and 300 healthy controls, including 200 patients with malignant nodules and 100 healthy controls previously investigated by ELISA for serum IL-2 and IL-6R levels.
The genotypic distribution of IL-2 and IL-6R did not differ between cases and controls. Six haplotypes were generated for IL-6R SNPs, none of the haplotypes showed significance with the risk for thyroid cancer. Significant correlation was observed between all investigated polymorphisms and the serologic levels of the corresponding interleukins. Patients who had the IL-2 gene TT genotype of rs2069762 had higher serum levels of IL-2. Individuals with the CC genotype of rs2228145, the GG genotype of the rs4845622 and the AA genotype of the rs6684439 correlated with a higher serum production of IL-6R.
We demonstrated that IL-2 SNPs rs2069762, IL-6R rs2228145, IL-6R rs4845622 and IL-6R rs6684439 are associated with differences in the concentrations of the respective interleukins and these concentrations suggesting they may have a clinical utility distinguishing patient with active-disease.
Role of interleukin-6 and pentraxin 3 as an early marker in Peyronie's disease
2017, Kaohsiung Journal of Medical Sciences
Citation Excerpt :
For example, IL-6 has been demonstrated to play a critical role in the pathogenesis of systemic sclerosis, an autoimmune connective tissue disorder characterized by fibrosis of the skin and internal organs [23]. Elevated IL-6 levels were detected in serum and synovial tissues of patients with rheumatoid arthritis and also in the serum of patients with inflammatory disorders including asthma, psoriasis, inflammatory bowel disease, and Crohn's disease [24–28]. PTX3 is a multifunctional fluid-phase pattern recognition receptor that links innate immunity, inflammation, and matrix deposition, and shows a unique pattern of regulation [29].
Inflammation is mechanistically involved in the development of Peyronie’s disease (PD). The aim of this study is to assess the relevance of serum pentraxin 3 (PTX3) and interleukin-6 (IL-6) concentrations in PD. The study enrolled 40 patients with PD in the acute phase and 40 healthy controls. Plasma PTX3 and IL-6 concentrations were evaluated in 40 patients in the acute phase of PD and 40 healthy controls by enzyme-linked immunosorbent assay. Serum concentrations of both PTX3 and IL-6 were significantly higher in the PD patients than in the control group (p = 0.001 and p = 0.001, respectively). There was a significant correlation between concentration of PTX3 and painful erections. IL-6 concentrations were significantly higher in patients with erectile dysfunction. IL-6 and PTX3 levels showed no correlation with age, serum C-reactive protein, degree of curvature, and disease duration. IL-6 trans-signaling and PTX3 amplification at the site of inflammation could have a role in pathophysiological mechanisms of PD. Biological drugs may be used for treatment during the acute phase of the disease based on this mechanism.
Alternative intronic polyadenylation generates the interleukin-6 trans-signaling inhibitor sgp130-E10
2014, Journal of Biological Chemistry
Citation Excerpt :
Although sgp130Fc inhibited STAT3 phosphorylation at concentrations of ∼1 nm, even 100 times more sgp130-E10Fc only reduced, but did not completely inhibit, STAT3 phosphorylation (Fig. 6D). Hyper-activation of gp130 by IL-6 trans-signaling is due to elevated levels of IL-6 and sIL-6R and was observed in many inflammatory disorders, e.g. in rheumatoid arthritis (20–22). IL-6 trans-signaling is crucial for the development and maintenance of rheumatoid arthritis (23, 24).
Interleukin (IL)-6 signals via a receptor complex composed of the signal-transducing β-receptor gp130 and the non-signaling membrane-bound or soluble IL-6 receptor α (IL-6R, sIL-6R), which is referred to as classic and trans-signaling, respectively. IL-6 trans-signaling is functionally associated with the development of chronic inflammatory diseases and cancer. Soluble gp130 (sgp130) variants are natural inhibitors of trans-signaling. Differential splicing yields sgp130 isoforms. Here, we describe that alternative intronic polyadenylation in intron 10 of the gp130 transcript results in a novel mRNA coding for an sgp130 protein isoform (sgp130-E10) of 70–80 kDa. The sgp130-E10 protein was expressed in vivo in human peripheral blood mononuclear cells. To assess the biological activity of sgp130-E10, we expressed this variant as Fc-tagged fusion protein (sgp130-E10Fc). Recombinant sgp130-E10Fc binds to a complex of IL-6 and sIL-6R, but not to IL-6 alone, and specifically inhibits IL-6 trans-signaling. Thus, it might play an important role in the regulation of trans-signaling in vivo.
Targeting interleukin-6 in inflammatory autoimmune diseases and cancers
2014, Pharmacology and Therapeutics
Citation Excerpt :
RA is an autoimmune disease that results in chronic, progressive inflammatory disorders of the joints and surrounding tissues, often leading to irreversible joint damage and systemic complications (Smolen et al., 2007). High levels of IL-6/sIL-6R complex in synovial fluids in patients with RA and juvenile RA are associated with joint destruction and disease progression (Keul et al., 1998). IL-6 produced by bone marrow stromal cells can induce the receptor activator of NF-κB ligand (RANKL), which is critical for the differentiation and activation of osteoclasts and bone resorption (Palmqvist et al., 2002).
Interleukin-6 (IL-6) is a pleiotropic cytokine with significant functions in the regulation of the immune system. As a potent pro-inflammatory cytokine, IL-6 plays a pivotal role in host defense against pathogens and acute stress. However, increased or deregulated expression of IL-6 significantly contributes to the pathogenesis of various human diseases. Numerous preclinical and clinical studies have revealed the pathological roles of the IL-6 pathway in inflammation, autoimmunity, and cancer. Based on the rich body of studies on biological activities of IL-6 and its pathological roles, therapeutic strategies targeting the IL-6 pathway are in development for cancers, inflammatory and autoimmune diseases. Several anti-IL-6/IL-6 receptor monoclonal antibodies developed for targeted therapy have demonstrated promising results in both preclinical studies and clinical trials. Tocilizumab, an anti-IL-6 receptor antibody, is effective in the treatment of various autoimmune and inflammatory conditions notably rheumatoid arthritis. It is the only IL-6 pathway targeting agent approved by the regulatory agencies for clinical use. Siltuximab, an anti-IL-6 antibody, has been shown to have potential benefits treating various human cancers either as a single agent or in combination with other chemotherapy drugs. Several other anti-IL-6-based therapies are also under clinical development for various diseases. IL-6 antagonism has been shown to be a potential therapy for these disorders refractory to conventional drugs. New strategies, such as combination of IL-6 blockade with inhibition of other signaling pathways, may further improve IL-6-targeted immunotherapy of human diseases.
Rational development and utilization of antibody-based therapeutic proteins in pediatrics
2013, Pharmacology and Therapeutics
Citation Excerpt :
Since JIA encompasses a group of clinically heterogeneous arthritides, the contribution of proinflammatory cytokines to disease formation is likely different among different subsets of patients (Ravelli & Martini, 2007). For example, studies have shown that IL-6 and IL-1 play a much larger role in the disease manifestations of systemic JIA than they do for polyarticular JRA (Keul et al., 1998; Pascual et al., 2005; Ruperto et al., 2012). This knowledge provides a biologic explanation as to why anti-TNFα therapies have been less effective in patients with systemic JIA (Kimura et al., 2005).
A large number of monoclonal antibody-based therapeutic proteins have emerged from the biopharmaceutical pipelines in recent years. Compared to small-molecule drugs, therapeutic proteins often confer a more targeted mechanism of action, with the potential for greater efficacy and fewer side effects. Over the recent decade, therapeutic proteins have gained an increasingly important place in the management of various diseases, including many of those that are referred to as “refractory” or “recalcitrant” to conventional therapies. In order to improve the well-being of pediatric patients and provide additional options for unmet medical needs, it is imperative to develop these innovative biotherapeutics for clinical use in children. This article provides an overview of the approved and emerging antibody-based therapeutic proteins with pediatric indications, the similarities and dissimilarities in pharmacokinetics, pharmacodynamics and immunogenicity of therapeutic proteins between children and adults, and strategies to develop therapeutic proteins in pediatric settings with emphasis on dose selection and rational use. In the context of a pediatric dosing strategy, the use of quantitative pharmacokinetic/pharmacodynamic modeling approaches to bridge the information gap between children and adults is also discussed.
Interleukin-6: From an inflammatory marker to a target for inflammatory diseases
2012, Trends in Immunology
Citation Excerpt :
Furthermore, blocking the IL-6R in wild-type mice reduces the development of arthritis in the CIA model [29], suggesting that this treatment could be used for clinical therapy. In addition to IL-6, the levels of sIL-6R are also elevated in RA and juvenile RA, and these levels are associated with joint destruction and disease progression [26,30], providing more evidence that IL-6 contributes to the disease. sIL-6R at sites of inflammation could confer IL-6 responsiveness to cells that do not express an IL-6R (e.g., osteoclasts and fibroblasts).
The incidence and diversity of chronic inflammatory diseases is increasing worldwide. However, the complexity of clinical symptoms has made it difficult to develop therapies that provide a substantial improvement for extended periods of time in a wide range of patient groups. Thus, there is a need for new therapies that target inflammatory responses without compromising immune defense. Interleukin (IL)-6, one of the first identified cytokines, has recently been recognized as a potential target in inflammatory disease. Here, I discuss how this cytokine has evolved from being a marker of inflammation to a successful target to control inflammation. I will summarize the results from the recent clinical studies using IL-6 receptor blockade, and describe potential mechanisms by which IL-6 can contribute to the progression of inflammatory diseases.

View all citing articles on Scopus

^f1: Correspondence to: P. Woo, Department of Molecular Pathology, University College London Medical School, The Windeyer Institute of Medical Sciences, 46 Cleveland Street, London W1P 6DB, UK; E-mail: [email protected]

View full text

Regular articleA POSSIBLE ROLE FOR SOLUBLE IL-6 RECEPTOR IN THE PATHOGENESIS OF SYSTEMIC ONSET JUVENILE CHRONIC ARTHRITIS

Abstract

Regular article
A POSSIBLE ROLE FOR SOLUBLE IL-6 RECEPTOR IN THE PATHOGENESIS OF SYSTEMIC ONSET JUVENILE CHRONIC ARTHRITIS