Abstract
Introduction
This study aims to test the serum levels of interleukin-33 (IL-33) and soluble ST2 (sST2) in patients with chronic kidney disease (CKD) and to evaluate their association with disease severity.
Methods
Sixty-nine patients with CKD were enrolled, disease severity was assessed, and clinical data were collected. Twelve healthy volunteers served as healthy individuals. Serum IL-33 and sST2 were tested by enzyme-linked immunosorbent assay.
Results
The patients were classified into five categories based on their estimated glomerular filtration rate (eGFR). No difference was found as to the serum concentration of IL-33 between CKD patients and healthy individuals (p = 0.656), while a higher serum level of sST2 was found in CKD patients (p = 0.003). The correlation analysis revealed a significant correlation between the serum level of sST2 and disease severity (r = 0.586; p < 0.001). A higher level of sST2 was found in CKD patients with elevated parathyroid hormone (p = 0.001). Serum sST2 correlated with parathyroid hormone (r = 0.412; p < 0.001), serum phosphorus (r = 0.545; p < 0.001), and serum calcium (r = −0.494; p < 0.001).
Conclusion
An elevated concentration of serum sST2 is found in CKD patients and correlates with disease severity. Serum sST2 may be also associated with parathyroid hormone disorder of CKD. The sST2 may have an important role in the development of CKD or as a marker of disease severity.
Similar content being viewed by others
References
Dinarello CA. Biologic basis for interleukin-1 in disease. Blood. 1996;87:2095–147.
Lohning M, Stroehmann A, Coyle AJ, Grogan JL, Lin S, Gutierrez-Ramos JC, Levinson D, Radbruch A, Kamradt T. T1/ST2 is preferentially expressed on murine Th2 cells, independent of interleukin 4, interleukin 5, and interleukin 10, and important for Th2 effector function. Proc Natl Acad Sci USA. 1998;95:6930–5.
Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK, Zurawski G, Moshrefi M, Qin J, Li X, Gorman DM, Bazan JF, Kastelein RA. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity. 2005;23:479–90.
Kakkar R, Lee RT. The IL-33/ST2 pathway: therapeutic target and novel biomarker. Nat Rev Drug Discov. 2008;7:827–40.
Carriere V, Roussel L, Ortega N, Lacorre DA, Americh L, Aguilar L, Bouche G, Girard JP. IL-33, the IL-1-like cytokine ligand for ST2 receptor, is a chromatin associated nuclear factor in vivo. Proc Natl Acad Sci USA. 2007;104:282–7.
Palmer G, Talabot-Ayer D, Lamacchia C, Toy D, Seemayer CA, Viatte S, Finckh A, Smith DE, Gabay C. Inhibition of interleukin-33 signaling attenuates the severity of experimental arthritis. Arthritis Rheum. 2009;60:738–49.
Pushparaj PN, Tay HK, H’ng SC, Pitman N, Xu D, McKenzie A, Liew FY, Melendez AJ. The cytokine interleukin-33 mediates anaphylactic shock. Proc Natl Acad Sci USA. 2009;106:9773–8.
Sanada S, Hakuno D, Higgins LJ, Schreiter ER, McKenzie AN, Lee RT. IL-33 and ST2 comprise a critical biomechanically induced and cardioprotective signaling system. J Clin Invest. 2007;117:1538–49.
Pastorelli L, Garg RR, Hoang SB, Spina L, Mattioli B, Scarpa M, Fiocchi C, Vecchi M, Pizarro TT. Epithelial-derived IL-33 and its receptor ST2 are dysregulated in ulcerative colitis and in experimental Th1/Th2 driven enteritis. PNAS. 2010;4:8017–22.
Mok MY, Huang FP, Ip WK, Lo Y, Wong FY, Chan EY, Lam KF, Xu D. Serum levels of IL-33 and soluble ST2 and their association with disease activity in systemic lupus erythematosus. Rheumatology. 2010;49:520–7.
Hung AM, Crawford DC, Griffin MR, Brown-Gentry K, Lipkowitz MS, Siew ED, Cavanaugh K, Lewis JB, Ikizler TA. CRP polymorphisms and progression of chronic kidney disease in African Americans. Clin J Am Soc Nephrol. 2010;5:24–33.
Tonelli M, Sacks F, Pfeffer M, Jhangri GS, Curhan G. Biomarkers of inflammation and progression of chronic kidney disease. Kidney Int. 2005;68:237–45.
Chiang CK, Hsu SP, Pai MF, Peng YS, Ho TI, Liu SH, Hung KY, Tsai TJ, Hsieh BS. Plasma interleukin-18 levels in chronic renal failure and continuous ambulatory peritoneal dialysis. Blood Purif. 2005;23:144–8.
Litjens NH, van Druningen CJ, Betjes MG. Progressive loss of renal function is associated with activation and depletion of naive T lymphocytes. Clin Immunol. 2006;118:83–91.
Sester U, Sester M, Hauk M, Kaul H, Kohler H, Girndt M. T-cell activation follows Th1 rather than Th2 pattern in haemodialysis patients. Nephrol Dial Transplant. 2000;15:1217–23.
Libetta C, Rampino T, Dal Canton A. Polarization of T-helper lymphocytes toward the Th2 phenotype in uremic patients. Am J Kidney Dis. 2001;38:286–95.
Torres VE. Treatment strategies and clinical trial design in ADPKD. Adv Chronic Kidney Dis. 2010;17:190–204.
Kato S, Chmielewski M, Honda H, Pecoits-Filho R, Matsuo S, Yuzawa Y, Tranaeus A, Stenvinkel P, Lindholm B. Aspects of immune dysfunction in end-stage renal disease. Clin J Am Soc Nephrol. 2008;3:1526–33.
Andress DL. Vitamin D in chronic kidney disease: a systemic role for selective vitamin D receptor activation. Kidney Int. 2006;69:33–43.
Saleh H, Eeles D, Hodge JM, Nicholson GC, Gu R, Pompolo S, Gillespie MT, Quinn JM. Interleukin-33, a target of parathyroid hormone and oncostatin M, increases osteoblastic matrix mineral deposition and inhibits osteoclast formation in vitro. Endocrinology. 2011;152:1911–22.
National Kidney Foundation (NKF) Kidney Disease Outcome Quality Initiative (K/DOQI) Advisory board: K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Kidney Disease Outcome Quality Initiative. Am. J. Kidney Dis. 2002;39:S1–246.
Carrero JJ, Yilmaz MI, Lindholm B, Stenvinkel P. Cytokine dysregulation in chronic kidney disease: how can we treat it. Blood Purif. 2008;26:291–9.
Brunner M, Krenn C, Roth G, Moser B, Dworschak M, Jensen-Jarolim E, Spittler A, Sautner T, Bonaros N, Wolner E, Boltz-Nitulescu G, Ankersmit HJ. Increased levels of soluble ST2 protein and IgG1 production in patients with sepsis and trauma. Intensive Care Med. 2004;30:1468–73.
Shimpo M, Morrow DA, Weinberg EO, Sabatine MS, Murphy SA, Antman EM, Lee RT. Serum levels of the interleukin-1 receptor family member ST2 predict mortality and clinical outcome in acute myocardial infarction. Circulation. 2004;109:2186–90.
Mueller T, Dieplinger B, Gegenhuber A, Poelz W, Pacher R, Haltmayer M. Increased plasma concentrations of soluble ST2 are predictive for 1-year mortality inpatients with acute destabilized heart failure. Clin Chem. 2008;54:752–6.
Bruneau S, Le Berre L, Herve C, Valanciute A, Kamal M, Naulet J, Tesson L, Foucher Y, Soulillou JP, Sahali D, Dantal J. Potential role of soluble ST2 protein in idiopathic nephrotic syndrome recurrence following kidney transplantation. Am J Kidney Dis. 2009;54:522–32.
Hayakawa H, Hayakawa M, Kume A, Tominaga S. Soluble ST2 blocks interleukin-33 signaling in allergic airway inflammation. J Biol Chem. 2007;282:26369–80.
Xu D, Jiang HR, Kewin P, Li Y, Mu R, Fraser AR, Pitman N, Kurowska-Stolarska M, McKenzie AN, McInnes IB, Liew FY. IL-33 exacerbates antigen-induced arthritis by activating mast cells. Proc Natl Acad Sci U S A. 2008;105:10913–8.
Dinarello CA. An IL-1 family member requires caspase-1 processing and signals through the ST2 receptor. Immunity. 2005;23:461–2.
Lavi-Moshayoff V, Wasserman G, Meir T, Silver J, Naveh-Many T. PTH increases FGF23 gene expression and mediates the high-FGF23 levels of experimental kidney failure: a bone parathyroid feedback loop. Am J Physiol Renal Physiol. 2010;299:F882–9.
Medici D, Razzaque MS, Deluca S, Rector TL, Hou B, Kang K, Goetz R, Mohammadi M, Kuro-O M, Olsen BR, Lanske B. FGF-23-Klotho signaling stimulates proliferation and prevents vitamin D induced apoptosis. J Cell Biol. 2008;182:459–65.
Raggatt LJ, Qin L, Tamasi J, Jefcoat Jr SC, Shimizu E, Selvamurugan N, Liew FY, Bevelock L, Feyen JH, Partridge NC. Interleukin-18 is regulated by parathyroid hormone and is required for its bone anabolic actions. J Biol Chem. 2008;283:6790–8.
Zaiss MM, Kurowska-Stolarska M, Böhm C, Gary R, Scholtysek C, Stolarski B, Reilly J, Kerr S, Millar NL, Kamradt T, McInnes IB, Fallon PG, David JP, Liew FY, Schett G. IL-33 shifts the balance from osteoclast to alternatively activated macrophage differentiation and protects from TNF-a-mediated bone loss. J Immunol. 2011;186:6097–105.
Acknowledgments
The present work was supported by a research grant from The First Affiliated Hospital of Harbin Medical University (2009B27) and Heilongjiang Provincial Health Bureau (2009-062). We appreciate the support provided by all colleagues in the study department.
Disclosure
All the authors declared no competing interests.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Bao, YS., Na, SP., Zhang, P. et al. Characterization of Interleukin-33 and Soluble ST2 in Serum and Their Association with Disease Severity in Patients with Chronic Kidney Disease. J Clin Immunol 32, 587–594 (2012). https://doi.org/10.1007/s10875-011-9622-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10875-011-9622-7