Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Arthritis Research & Therapy
Published in: Arthritis Research & Therapy 1/2018

Open Access 01-12-2018 | Research article

IL-1 family cytokines and soluble receptors in systemic lupus erythematosus

Authors: Paola Italiani, Maria Laura Manca, Francesca Angelotti, Daniela Melillo, Federico Pratesi, Ilaria Puxeddu, Diana Boraschi, Paola Migliorini

Published in: Arthritis Research & Therapy | Issue 1/2018

Login to get access

Abstract

Background

Dysregulated production of cytokines has a critical role in systemic lupus. The aim of this work is to identify, by a comprehensive analysis of IL-1 family cytokines and receptors in serum, correlation between cytokines/receptors’ levels and the clinical and serological features of the disease.

Methods

A full clinical evaluation was performed in 74 patients with systemic lupus erythematosus (SLE). C3, C4, anti-dsDNA and anti-C1q antibodies were measured. Cytokines of the IL-1 family (IL-1α, IL-1β, IL-33, IL-18), soluble receptors (sIL-1R1, sIL-1R2, sIL-1R3, ST2/sIL-1R4) and antagonists (IL-1Ra, IL-18 binding protein (IL-18BP)) were measured in serum by multiarray ELISA. Free IL-18 was calculated as the amount of IL-18 not inhibited by IL-18BP. Data were analysed by non-parametric tests and by multivariate analysis, using partial least squares (PLS) models.

Results

Total IL-18, IL-18BP, sIL-1R4 and IL-1Ra levels were higher in SLE vs. controls. Total and free IL-18 and sIL-1R4 were higher in patients with active vs. inactive disease and correlated with ECLAM, anti-C1q and anti-dsDNA antibodies. sIL-1R2 was higher in patients with inactive disease, was negatively correlated with ECLAM and anti-C1q antibodies and was positively correlated with C3 levels. PLS identified sIL-1R4, sIL-1R2 and anti-dsDNA as variables distinguishing patients with active from those with inactive disease; sIL-1R4, IL-18BP and anti-dsDNA identified patients with active nephritis; sIL-1R4, C3, IL-18 and free IL-18 identified patients with haematological involvement.

Conclusion

The data support the use of IL-18, sIL-1R2 and sIL-1R4 as biomarkers of disease activity and organ involvement, and suggest that failure in the inhibition of IL-1 activation may be a critical event in the active stages of SLE.
Literature
1.
2.
Novick D, Kim SH, Fantuzzi G, Reznikov LL, Dinarello CA, Rubinstein M. Interleukin-18 binding protein: a novel modulator of the Th1 cytokine response. Immunity. 1999;10:127–36.CrossRefPubMed
3.
Boraschi D, Dinarello CA. IL-18 in autoimmunity: review. Eur Cytokine Netw. 2006;17:224–52.PubMed
4.
Netea MG, van de Veerdonk FL, van der Meer JW, Dinarello CA, Joosten LA. Inflammasome-independent regulation of IL-1-family cytokines. Annu Rev Immunol. 2015;33:49–77.CrossRefPubMed
5.
6.
Cavalli G, Dinarello CA. Treating rheumatological diseases and co-morbidities with interleukin-1 blocking therapies. Rheumatology (Oxford). 2015;54:2134–44.PubMedPubMedCentral
7.
8.
Liew FY, Pitman NI, McInnes IB. Disease-associated functions of IL-33: the new kid in the IL-1 family. Nat Rev Immunol. 2010;10:103–10.CrossRefPubMed
9.
Lott JM, Sumpter TL, Turnquist HR. New dog and new tricks: evolving roles for IL-33 in type 2 immunity. J Leukoc Biol. 2015;97:1037–48.CrossRefPubMed
10.
Gordon ED, Simpson LJ, Rios CL, Ringel L, Lachowicz-Scroggins ME, Peters MC, et al. Alternative splicing of interleukin-33 and type 2 inflammation in asthma. Proc Natl Acad Sci USA. 2016;113:8765–70.CrossRefPubMedPubMedCentral
11.
Esfandiari E, McInnes IB, Lindop G, Huang FP, Field M, Komai-Koma M, et al. A proinflammatory role of IL-18 in the development of spontaneous autoimmune disease. J Immunol. 2001;167:5338–47.CrossRefPubMed
12.
Bossù P, Del Giudice E, Ciaramella A, Neumann D, Boraschi D. IL-18 and IL-18 receptors in the development of autoimmunity. Eur Cytokine Netw. 2000;11:515–6.PubMed
13.
Faust J, Menke J, Kriegsmann J, Kelley VR, Mayet WJ, Galle PR, et al. Correlation of renal tubular epithelial cell-derived interleukin-18 up-regulation with disease activity in MRL-Faslpr mice with autoimmune lupus nephritis. Arthritis Rheum. 2002;46:3083–95.CrossRefPubMed
14.
Bossù P, Neumann D, Del Giudice E, Ciaramella A, Gloaguen I, Fantuzzi G, et al. IL-18 cDNA vaccination protects mice from spontaneous lupus-like autoimmune disease. Proc Natl Acad Sci USA. 2003;100:14181–6.CrossRefPubMedPubMedCentral
15.
Hu D, Liu X, Chen S, Bao C. Expressions of IL-18 and its binding protein in peripheral blood leukocytes and kidney tissues of lupus nephritis patients. Clin Rheumatol. 2010;29:717–21.CrossRefPubMed
16.
Tucci M, Quatraro C, Lombardi L, Pellegrino C, Dammacco F, Silvestris F. Glomerular accumulation of plasmacytoid dendritic cells in active lupus nephritis: role of interleukin-18. Arthritis Rheum. 2008;58:251–62.CrossRefPubMed
17.
Novick D, Elbirt D, Miller G, Dinarello CA, Rubinstein M, Sthoeger ZM. High circulating levels of free interleukin-18 in patients with active SLE in the presence of elevated levels of interleukin-18 binding protein. J Autoimmun. 2010;34:121–6.CrossRefPubMed
18.
Migliorini P, Anzilotti C, Pratesi F, Quattroni P, Bargagna M, Dinarello CA, et al. Serum and urinary levels of IL-18 and its inhibitor IL-18BP in systemic lupus erythematosus. Eur Cytokine Netw. 2010;21:264–71.PubMed
19.
Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997;40:1725.CrossRefPubMed
20.
Mosca M, Chimenti D, Pratesi F, Baldini C, Anzilotti C, Bombardieri S, et al. Prevalence and clinico-serological correlations of anti-alpha-enolase, anti-C1q, and anti-dsDNA antibodies in patients with systemiclupus erythematosus. J Rheumatol. 2006;33:695–7.PubMed
21.
Siegert CE, Daha MR, van der Voort EA, Breedveld FC. IgG and IgA antibodies to the collagen-like region of C1q in rheumatoid vasculitis. Arthritis Rheum. 1990;33:1646–54.CrossRefPubMed
22.
Novick D, Schwartsburd B, Pinkus R, Suissa D, Belzer I, Sthoeger Z, et al. A novel IL-18BP ELISA shows elevated serum IL-18BP in sepsis and extensive decrease of free IL-18. Cytokine. 2001;14:334–42.CrossRefPubMed
23.
Abdi H, Williams LJ. Partial least squares methods: partial least squares correlation and partial least square regression. Methods Mol Biol. 2013;930:549–79.CrossRefPubMed
24.
Koenig KF, Groeschl I, Pesickova SS, Tesar V, Eisenberger U, Trendelenburg M. Serum cytokine profile in patients with active lupus nephritis. Cytokine. 2012;60:410–6.CrossRefPubMed
25.
Kahlenberg JM, Carmona-Rivera C, Smith CK, Kaplan MJ. Neutrophil extracellular trap-associated protein activation of the NLRP3 inflammasome is enhanced in lupus macrophages. J Immunol. 2013;190:1217–26.CrossRefPubMed
26.
Shan NN, Zhu XJ, Peng J, Qin P, Zhuang XW, Wang HC, et al. Interleukin 18 and interleukin 18 binding protein in patients with idiopathic thrombocytopenic purpura. Br J Haematol. 2009;144:755–61.CrossRefPubMed
27.
Suzuki H, Takemura H, Kashiwagi H. Interleukin-1 receptor antagonist inpatients with active systemic lupus erythematosus. Enhanced production by monocytes and correlation with disease activity. Arthritis Rheum. 1995;38:1055–9.CrossRefPubMed
28.
Chang DM. Interleukin-1 and interleukin-1 receptor antagonist in systemic lupus erythematosus. Immunol Invest. 1997;26:649–59.CrossRefPubMed
29.
O'Gorman WE, Kong DS, Balboni IM, Rudra P, Bolen CR, Ghosh D, et al. Mass cytometry identifies a distinct monocyte cytokine signature shared by clinically heterogeneous pediatric SLE patients. J Autoimmun. 2017;(16)30412-7.
30.
Capper ER, Maskill JK, Gordon C, Blakemore AI. Interleukin (IL)-10, IL-1ra andIL-12 profiles in active and quiescent systemic lupus erythematosus: could longitudinal studies reveal patient subgroups of differing pathology? Clin Exp Immunol. 2004;138:348–56.CrossRefPubMedPubMedCentral
31.
Sturfelt G, Roux-Lombard P, Wollheim FA, Dayer JM. Low levels of interleukin-1 receptor antagonist coincide with kidney involvement in systemic lupus erythematosus. Br J Rheumatol. 1997;36:1283–9.CrossRefPubMed
32.
33.
Uchikawa S, Yoda M, Tohmonda T, Kanaji A, Matsumoto M, Toyama Y, et al. ADAM17 regulates IL-1 signaling by selectively releasing IL-1 receptor type 2 from the cell surface. Cytokine. 2015;71:238–45.CrossRefPubMed
34.
Du Y, Wu X, Chen M, Wang W, Xv W, Ye L, et al. Elevated semaphorin 5A in systemic lupus erythematosus is in association with disease activity and lupus nephritis. Clin Exp Immunol. 2017;188:234–42.CrossRefPubMed
35.
Arend WP, Malyak M, Smith MF Jr, Whisenand TD, Slack JL, Sims JE, et al. Binding of IL-1 alpha, IL-1 beta, and IL-1 receptor antagonist by soluble IL-1 receptors and levels of soluble IL-1 receptors in synovial fluids. J Immunol. 1994;153:4766–74.PubMed
36.
Elzinga BM, Twomey C, Powell JC, Harte F, McCarthy JV. Interleukin-1 receptor type 1 is a substrate for γ-secretase-dependent regulated intramembrane proteolysis. J Biol Chem. 2009;284:1394–409.CrossRefPubMed
37.
Yamada M, Nishizawa M, Nakatake R, Habara K, Yoshida H, Ozaki T, et al. Characterization of alternatively spliced isoforms of the type I interleukin-1 receptor on iNOS induction in rate hepatocytes. Nitric Oxide. 2007;17:98–105.CrossRefPubMed
38.
Kuroiwa K, Arai T, Okazaki H, Minota S, Tominaga S. Identification of human ST2 protein in the sera of patients with autoimmune diseases. Biochem Biophys Res Commun. 2001;284:1104–8.CrossRefPubMed
39.
Palomo J, Dietrich D, Martin P, Palmer G, Gabay C. The interleukin (IL)-1cytokine family–balance between agonists and antagonists in inflammatory diseases. Cytokine. 2015;76:25–37.CrossRefPubMed
40.
Mok MY, Huang FP, Ip WK, Lo Y, Wong FY, Chan EY, et al. Serum levels of IL-33 and soluble ST2 and their association with disease activity in systemic lupus erythematosus. Rheumatology (Oxford). 2010;49:520–7.CrossRefPubMed
41.
Zhang Z, Wang H, Zhang L, Crew R, Zhang N, Liu X, et al. Serum levels of soluble ST2 and IL-10 are associated with disease severity in patients with IgA nephropathy. J Immunol Res. 2016;2016:6540937.PubMedPubMedCentral
42.
Griesenauer B, Paczesny S. The ST2/IL-33 Axis in Immune Cells during Inflammatory Diseases. Front Immunol. 2017;8:475.
43.
De la Fuente M, MacDonald TT, Hermoso MA. The IL-33/ST2 axis: role in health and disease. Cytokine Growth Factor Rev. 2015;26:615–23.CrossRefPubMed
44.
Wettersten N, Maisel AS. Biomarkers for heart failure: an update for practitioners of internal medicine. Am J Med. 2016;129:560–7.CrossRefPubMed
45.
Yang Z, Liang Y, Xi W, Li C, Zhong R. Association of increased serum IL-33 levels with clinical and laboratory characteristics of systemic lupus erythematosus in Chinese population. Clin Exp Med. 2011;11:75–80.CrossRefPubMed
46.
Yu SL, Wong CK, Tam LS. The alarmin functions of high-mobility group box-1 and IL-33 in the pathogenesis of systemic lupus erythematosus. Expert Rev Clin Immunol. 2013;9:739–49.CrossRefPubMed
47.
Li P, Lin W, Zheng X. IL-33 neutralization suppresses lupus disease in lupus-prone mice. Inflammation. 2014;37:824–32.CrossRefPubMed
48.
49.
Mistry P, Kaplan MJ. Cell death in the pathogenesis of systemic lupus erythematosus and lupus nephritis. Clin Immunol. 2017;185:59-73.
Metadata
Title
IL-1 family cytokines and soluble receptors in systemic lupus erythematosus
Authors
Paola Italiani
Maria Laura Manca
Francesca Angelotti
Daniela Melillo
Federico Pratesi
Ilaria Puxeddu
Diana Boraschi
Paola Migliorini
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Arthritis Research & Therapy / Issue 1/2018
Electronic ISSN: 1478-6362
DOI
https://doi.org/10.1186/s13075-018-1525-z

Other articles of this Issue 1/2018

Arthritis Research & Therapy 1/2018 Go to the issue

Research article

Effects of transitional care on self-care, readmission rates, and quality of life in adult patients with systemic lupus erythematosus: a randomized controlled trial

Research article

Metabolomic alterations associated with Behçet’s disease

Research article

Association of serum levels of fibrosis-related biomarkers with disease activity in patients with IgG4-related disease

Research

Prevalence of comorbidities in systemic sclerosis versus rheumatoid arthritis: a comparative, multicenter, matched-cohort study

Research article

The effects of upper and lower limb exercise on the microvascular reactivity in limited cutaneous systemic sclerosis patients

Research article

Resolution of synovitis and arrest of catabolic and anabolic bone changes in patients with psoriatic arthritis by IL-17A blockade with secukinumab: results from the prospective PSARTROS study

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits