Increased soluble ST2 and IL‑4 serum levels are associated with disease severity in patients with membranous nephropathy

Zhang,Zhihui; Liu,Xiaolei; Wang,Haifeng; Qu,Zhihui; Crew,Rebecca; Zhang,Nan; Jiang,Yanfang

doi:10.3892/mmr.2017.8130

Increased soluble ST2 and IL‑4 serum levels are associated with disease severity in patients with membranous nephropathy

Authors:
- Zhihui Zhang
- Xiaolei Liu
- Haifeng Wang
- Zhihui Qu
- Rebecca Crew
- Nan Zhang
- Yanfang Jiang
View Affiliations

Affiliations: Genetic Diagnosis Center, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China, Key Laboratory of Zoonoses Research, Ministry of Education, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China, Department of Nephrology, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China, University of Oklahoma Health Sciences Center, Oklahoma, OK 73104, USA
Published online on: November 22, 2017 https://doi.org/10.3892/mmr.2017.8130
Pages: 2778-2786

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The interleukin (IL)‑33/suppression of tumorigenicity 2 (ST2) axis regulates Th2 reactivity, and ST2 is the receptor for IL‑33. In this study, the roles of IL‑33 and soluble ST2 (sST2) in the pathogenesis of membranous nephropathy (MN), and their association with disease severity were evaluated. Serum levels of IL‑33 and sST2 in 93 patients, and 34 healthy controls (HCs) were measured by enzyme‑linked immunosorbent assays. Clinical characteristics were recorded and the estimated glomerular filtration rates (eGFRs) were computed. In addition, the association between serum IL‑33 and sST2 levels, and clinical measurements in patients with MN was analyzed. No difference in the serum levels of IL‑33 was identified between the patients with MN and HCs. However, the serum levels of sST2 were considerably higher in the MN patients compared with in the HCs at every stage. Higher concentrations of serum IL‑2, IL‑4, IL‑10, IL‑17A, and IFN‑γ were measured in the MN patients compared with in the HCs. Serum sST2 concentrations were negatively correlated with IL‑4 concentrations in the patients with MN. Furthermore, serum sST2 levels were negatively correlated with the eGFRs and serum calcium levels. Serum sST2 levels, but not IL‑33 levels, were positively correlated with the 24‑h urine protein and serum phosphorus levels. Following treatment, serum sST2 levels were considerably reduced, whereas serum IL‑4 and IL‑10 levels were significantly increased. These data suggest that sST2 and IL‑4, but not IL‑33, contribute to the pathogenesis of MN.

View Figures

View References

1	Glassock RJ: The pathogenesis of idiopathic membranous nephropathy: A 50-year odyssey. Am J Kidney Dis. 56:157–167. 2010. View Article : Google Scholar : PubMed/NCBI
2	Ronco P and Debiec H: Pathogenesis of membranous nephropathy: Recent advances and future challenges. Nat Rev Nephrol. 8:203–213. 2012. View Article : Google Scholar : PubMed/NCBI
3	Cattran D: Management of membranous nephropathy: When and what for treatment. J Am Soc Nephrol. 16:1188–1194. 2005. View Article : Google Scholar : PubMed/NCBI
4	Cattran DC: Idiopathic membranous glomerulonephritis. Kidney Int. 59:1983–1994. 2001. View Article : Google Scholar : PubMed/NCBI
5	Honkanen E, Törnroth T and Grönhagen-Riska C: Natural history, clinical course and morphological evolution of membranous nephropathy. Nephrol Dial Transplant. 7 Suppl 1:S35–S41. 1992.
6	Glassock RJ: The treatment of idiopathic membranous nephropathy: A dilemma or a conundrum? Am J Kidney Dis. 44:562–566. 2004. View Article : Google Scholar : PubMed/NCBI
7	Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK, Zurawski G, Moshrefi M, Qin J, Li X, et al: IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptorrelated protein ST2 and induces T helper type 2-associated cytokines. Immunity. 23:479–490. 2005. View Article : Google Scholar : PubMed/NCBI
8	Alves-Filho JC, Sônego F, Souto FO, Freitas A, Verri WA Jr, Auxiliadora-Martins M, Basile-Filho A, McKenzie AN, Xu D, Cunha FQ and Liew FY: Interleukin-33 attenuates sepsis by enhancing neutrophil influx to the site of infection. Nat Med. 16:708–712. 2010. View Article : Google Scholar : PubMed/NCBI
9	Löhning M, Stroehmann A, Coyle AJ, Grogan JL, Lin S, Gutierrez-Ramos JC, Levinson D, Radbruch A and 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. 95:pp. 6930–6935. 1998; View Article : Google Scholar : PubMed/NCBI
10	Sanada S, Hakuno D, Higgins LJ, Schreiter ER, McKenzie AN and Lee RT: IL-33 and ST2 comprise a critical biomechanically induced and cardioprotective signaling system. J Clin Invest. 117:1538–1549. 2007. View Article : Google Scholar : PubMed/NCBI
11	Palmer G, Talabot-Ayer D, Lamacchia C, Toy D, Seemayer CA, Viatte S, Finckh A, Smith DE and Gabay C: Inhibition of interleukin-33 signaling attenuates the severity of experimental arthritis. Arthritis Rheum. 60:738–749. 2009. View Article : Google Scholar : PubMed/NCBI
12	Pastorelli L, De Salvo C, Cominelli MA, Vecchi M and Pizarro TT: Novel cytokine signaling pathways in inflammatory bowel disease: Insight into the dichotomous functions of IL-33 during chronic intestinal inflammation. Therap Adv Gastroenterol. 4:311–323. 2011. View Article : Google Scholar : PubMed/NCBI
13	Mok MY, Huang FP, Ip WK, Lo Y, Wong FY, Chan EY, Lam KF and Xu D: Serum levels of IL-33 and soluble ST2 and their association with disease activity in systemic lupus erythematosus. Rheumatology (Oxford). 49:520–527. 2010. View Article : Google Scholar : PubMed/NCBI
14	Kalavrizioti D, Gerolymos M, Rodi M, Kalliakmani P, Provatopoulou S, Eleftheriadis T, Mouzaki A and Goumenos DS: T helper (Th)-cytokines in the urine of patients with primary glomerulonephritis treated with immunosuppressive drugs: Can they predict outcome? Cytokine. 76:260–269. 2015. View Article : Google Scholar : PubMed/NCBI
15	Kuroki A, Iyoda M, Shibata T and Sugisaki T: Th2 cytokines increase and stimulate B cells to produce IgG4 in idiopathic membranous nephropathy. Kidney Int. 68:302–310. 2005. View Article : Google Scholar : PubMed/NCBI
16	Morgan E, Varro R, Sepulveda H, Ember JA, Apgar J, Wilson J, Lowe L, Chen R, Shivraj L, Agadir A, et al: Cytometric bead array: A multiplexed assay platform with applications in various areas of biology. Clin Immunol. 110:252–266. 2004. View Article : Google Scholar : PubMed/NCBI
17	Tárnok A, Hambsch J, Chen R and Varro R: Cytometric bead array to measure six cytokines in twenty-five microliters of serum. Clin Chem. 49:1000–1002. 2003. View Article : Google Scholar : PubMed/NCBI
18	Barksby HE, Lea SR, Preshaw PM and Taylor JJ: The expanding family of interleukin-1 cytokines and their role in destructive inflammatory disorders. Clin Exp Immunol. 149:217–225. 2007. View Article : Google Scholar : PubMed/NCBI
19	Liew FY, Pitman NI and McInnes IB: Disease-associated functions of IL-33: The new kid in the IL-1 family. Nat Rev Immunol. 10:103–110. 2010. View Article : Google Scholar : PubMed/NCBI
20	Wang J, Cai Y, Ji H, Feng J, Ayana DA, Niu J and Jiang Y: Serum IL-33 levels are associated with liver damage in patients with chronic hepatitis B. J Interferon Cytokine Res. 32:248–253. 2012. View Article : Google Scholar : PubMed/NCBI
21	Yang Z, Liang Y, Xi W, Li C and Zhong R: Association of increased serum IL-33 levels with clinical and laboratory characteristics of systemic lupus erythematosus in Chinese population. Clin Exp Med. 11:75–80. 2011. View Article : Google Scholar : PubMed/NCBI
22	Hayakawa H, Hayakawa M, Kume A and Tominaga S: Soluble ST2 blocks interleukin-33 signaling in allergic airway inflammation. J Biol Chem. 282:26369–26380. 2007. View Article : Google Scholar : PubMed/NCBI
23	Dinarello CA: An IL-1 family member requires caspase-1 processing and signals through the ST2 receptor. Immunity. 23:461–462. 2005. View Article : Google Scholar : PubMed/NCBI
24	Brunner M, Krenn C, Roth G, Moser B, Dworschak M, Jensen-Jarolim E, Spittler A, Sautner T, Bonaros N, Wolner E, et al: Increased levels of soluble ST2 protein and IgG1 production in patients with sepsis and trauma. Intensive Care Med. 30:1468–1473. 2004. View Article : Google Scholar : PubMed/NCBI
25	Shimpo M, Morrow DA, Weinberg EO, Sabatine MS, Murphy SA, Antman EM and Lee RT: Serum levels of the interleukin-1 receptor family member ST2 predict mortality and clinical outcome in acute myocardial infarction. Circulation. 109:2186–2190. 2004. View Article : Google Scholar : PubMed/NCBI
26	Mueller T, Dieplinger B, Gegenhuber A, Poelz W, Pacher R and Haltmayer M: Increased plasma concentrations of soluble ST2 are predictive for 1-year mortality in patients with acute destabilized heart failure. Clin Chem. 54:752–756. 2008. View Article : Google Scholar : PubMed/NCBI
27	Rodrigues-Díez R, Aroeira LS, Orejudo M, Bajo MA, Heffernan JJ, Rodrigues-Díez RR, Rayego-Mateos S, Ortiz A, Gonzalez-Mateo G, López-Cabrera M, et al: IL-17A is a novel player in dialysis-induced peritoneal damage. Kindey Int. 86:303–315. 2014. View Article : Google Scholar
28	Griesenauer B and Paczesny S: The ST2/IL-33 axis in immune cells during inflammatory diseases. Front Immunol. 8:4752017. View Article : Google Scholar : PubMed/NCBI
29	Hayakawa H, Hayakawa M, Kume A and Tominaga S: Soluble ST2 blocks IL-33 signaling in allergic airway inflammation. J Biol Chem. 282:26369–26380. 2007. View Article : Google Scholar : PubMed/NCBI
30	Yin H, Li XY, Liu T, Yuan BH, Zhang BB, Hu SL, Gu HB, Jin XB and Zhu JY: Adenovirus-mediated delivery of soluble ST2 attenuates ovalbumin-induced allergic asthma in mice. Clin Exp Immunol. 170:1–9. 2012. View Article : Google Scholar : PubMed/NCBI
31	Prunotto M, Carnevali ML, Candiano G, Murtas C, Bruschi M, Corradini E, Trivelli A, Magnasco A, Petretto A, Santucci L, et al: Autoimmunity in membranous nephropathy targets aldose reductase and SOD2. J Am Soc Nephrol. 21:507–519. 2010. View Article : Google Scholar : PubMed/NCBI
32	Lavi-Moshayoff V, Wasserman G, Meir T, Silver J and 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. 299:F882–F889. 2010. View Article : Google Scholar : PubMed/NCBI
33	Shimada T, Hasegawa H, Yamazaki Y, Muto T, Hino R, Takeuchi Y, Fujita T, Nakahara K, Fukumoto S and Yamashita T: FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res. 19:429–435. 2004. View Article : Google Scholar : PubMed/NCBI
34	Torres VE: Treatment strategies and clinical trial design in ADPKD. Adv Chronic Kidney Dis. 17:190–204. 2010. View Article : Google Scholar : PubMed/NCBI
35	Bao YS, Na SP, Zhang P, Jia XB, Liu RC, Yu CY, Mu SH and Xie RJ: 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. View Article : Google Scholar : PubMed/NCBI