Abstract
Objective
This study aimed to investigate the immunological relationship and the mechanism between tonsillar inflammation and immunoglobulin A nephropathy (IgAN).
Subjects
Tonsillar mononuclear cells (TMCs) were prepared from 13 patients with IgAN and 13 patients with chronic tonsillitis but without renal disease. The human renal tubular epithelial cell (TEC) line, HK-2, was used to test the effects of secretions from the TMCs.
Methods
Phytohemagglutinin (PHA) was used to induce the inflammatory responses in TMCs. The secretions from TMCs, stimulated with or without PHA, were collected and applied to HK-2 cells. The proliferation, apoptosis, and epithelial–mesenchymal transition (EMT) of HK-2 cells were evaluated. The expression of key components during apoptosis and EMT was measured.
Results
The secretions from PHA-stimulated IgAN TMCs significantly inhibited proliferation, promoted apoptosis, and down-regulated Bcl-2 in HK-2 cells (P < 0.05) in time- and concentration-dependent manners. They also modulated the expression of key components during EMT, E-cadherin and α-SMA (P < 0.05).
Conclusions
The secretions from PHA-stimulated IgAN TMCs can cause the inhibition of proliferation, promotion of apoptosis, down-regulation of Bcl-2, and EMT effects in HK-2 TECs, which may reflect the in-vivo remote modulation of functions of renal TECs by tonsillar inflammation.
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References
Tomino Y, Endoh M, Nomoto Y, Sakai H. Immunoglobulin A1 and IgA nephropathy. N Engl J Med. 1981;305:1159–60.
Nishi S. The prognosis of IgA nephropathy–favorable or poor? Intern Med. 2001;40:679–80.
Kobayashi Y, Tateno S, Hiki Y, Shigematsu H. IgA nephropathy: prognostic significance of proteinuria and histological alterations. Nephron. 1983;34:146–53.
Feehally J, Beattie TJ, Brenchley PEC, Coupes BM, Mallick NP, Postlethwaite RJ. Sequential study of the IgA system in relapsing IgA nephropathy. Kidney Int. 1986;30:924–31.
Emancipator SN, Gallo GR, Lamm ME. Experimental IgA nephropathy induced by oral immunization. J Exp Med. 1983;157:572–82.
Kodama S, Suzuki M, Arita M, Mogi G. Increase in tonsillar germinal centre B-1 cell numbers in IgA nephropathy (IgAN) patients and reduced susceptibility to Fas-mediated apoptosis. Clin Exp Immunol. 2001;123:301–8.
Inoue T, Sugiyama H, Kikumoto Y, et al. Downregulation of the beta1,3- galactosyltransferase gene in tonsillar B lymphocytes and aberrant lectin bindings to tonsillar IgA as a pathogenesis of IgA nephropathy. Contrib Nephrol. 2007;157:120–4.
Liu H, Peng Y, Liu F, Xiao W, Zhang Y, Li W. Expression of IgA class switching gene in tonsillar mononuclear cells in patients with IgA nephropathy. Inflamm Res. 2011;60:869–78.
Tokuda M, Shimizu J, Sugiyama N, et al. Direct evidence of the production of IgA by tonsillar lymphocytes and the binding of IgA to the glomerular mesangium of IgA nephropathy patients. Acta Otolaryngol. 1996;523 Suppl:182–4.
Hiki Y, Horie A, Yasuda Y, Iwase H, Sugiyama S. IgA nephropathy and tonsils–an approach from the structure of IgA1 produced by tonsillar lymphocytes. Acta Otolaryngol. 2004;555 Suppl:28–31.
Sato M, Hotta O, Tomioka S, et al. Cohort study of advanced IgA nephropathy: efficacy and limitations of corticosteroids with tonsillectomy. Nephron Clin Pract. 2003;93:137–45.
Huang H. Relationship between the Pathogenesis of IgA Nephropathy and the Palatine Tonsils. Ph. D. Dissertation, Central South University, Changsha, China. 2007.
Lee TW, Park JK, Ahn JH, Ihm CG, Kim MJ. Role of mononuclear cells of IgA nephropathy on ICAM-1 expression in mesangial cells. Korean J Intern Med. 1998;13:27–32.
Lee TW, Ahn JH, Park JK, Ihm CG, Kim MJ. Tumor necrosis factor alpha from peripheral blood mononuclear cells of IgA nephropathy and mesangial cell proliferation. Korean J Intern Med. 1994;9:1–8.
Ichinohe S, Hussain IR, Johnston SL. Cytokine production of RSV/PHA-stimulated tonsillar mononuclear cells: influences of age and atopy. Eur Respir J. 2003;22:317–22.
Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983;65:55–63.
Thiagarajan P, Tait JF. Binding of annexin V/placental anticoagulant protein I to platelets. Evidence for phosphatidylserine exposure in the procoagulant response of activated platelets. J Biol Chem. 1990;265:17420–3.
Dachary PJ, Freyssinet JM, Pasquet JM, Carron JC, Nurden AT. Annexin V as a probe of aminophospholipid exposure and platelet membrane vesiculation: a flow cytometry study showing a role for free sulfhydryl groups. Blood. 1993;81:2554–65.
Korsmeyer SJ, Shutter JR, Veis DJ, Merry DE, Oltvai ZN. Bcl-2/Bax: a rheostat that regulates an anti-oxidant pathway and cell death. Semin Cancer Biol. 1993;4:327–32.
Reed JC, Miyashita T, Krajewski S, et al. Bcl-2 family proteins and the regulation of programmed cell death in leukemia and lymphoma. Cancer Treat Res. 1996;84:31–72.
Kuki K, Gotoh H, Hayashi M, et al. Immunity of tonsil and IgA nephropathy—relationship between IgA nephropathy and tonsillitis. Acta Otolaryngol. 2004;555 Suppl:6–9.
Fujieda S, Suzuki S, Sunaga H, et al. Induction of IgA against Haemophilus parainfluenzae antigens in tonsillar mononuclear cells from patients with IgA nephropathy. Clin Immunol. 2000;95:235–43.
Fujieda S, Suzuki S, Sunaga H, et al. Production of interferon-gamma by tonsillar mononuclear cells in IgA nephropathy patients. Acta Otolaryngol. 2000;120:649–54.
Zheng L, Sinniah R, Hsu SIH. Renal cell apoptosis and proliferation may be linked to nuclear factor-kappaB activation and expression of inducible nitric oxide synthase in patients with lupus nephritis. Hum Pathol. 2006;37:637–47.
Devarajan P. Cellular and molecular derangements in acute tubular necrosis. Curr Opin Pediatr. 2005;17:193–9.
Isaka Y, Suzuki C, Abe T, et al. Bcl-2 protects tubular epithelial cells from ischemia/reperfusion injury by dual mechanisms. Transplant Proc. 2009;41:52–4.
Korsmeyer SJ. BCL-2 gene family and the regulation of programmed cell death. Cancer Res. 1999;59:1693–700.
Chevalier RL, Kim A, Thornhill BA, Wolstenholme JT. Recovery following relief of unilateral ureteral obstruction in the neonatal rat. Kidney Int. 1999;55:793–807.
Bogenschutz O, Bohle A, Batz C, et al. IgA nephritis: on the importance of morphological and clinical parameters in the long-term prognosis of 239 patients. Am J Nephrol. 1990;10:137–47.
Strutz F, Okada H, Lo CW, Danoff T, Carone RL, Tomaszewski JE, Neilson EG. Identification and characterization of a fibroblast marker: FSP1. J Cell Biol. 1995;130:393–405.
Zeisberg M, Kalluri R. The role of epithelial-to-mesenchymal transition in renal fibrosis. J Mol Med. 2004;82:175–81.
Huang H, Peng Y, Liu F, Lei H. Is IgA nephropathy induced by abnormalities of CD4 + CD25 + Treg cells in the tonsils? Med Hypotheses. 2007;69:410–3.
Yang J, Liu Y. Dissection of key events in tubular epithelial to myofibroblast transition and its implications in renal interstitial fibrosis. Am J Pathol. 2001;159:1465–75.
Zavadil J, Bottinger EP. TGF-beta and epithelial-to-mesenchymal transitions. Oncogene. 2005;24:5764–74.
Kawaguchi M, Sakai T, Sakamaki A, et al. Expanded primary T nodules in the palatine tonsils from patients with IgA nephropathy. Acta Otolaryngol. 1993;508 Suppl:36–42.
Bene MC, Faure G. Hurault de Ligny B, et al. Immunoglobulin A nephropathy. Quantitative immunohistomorphometry of the tonsillar plasma cells evidences an inversion of the immunoglobulin A versus immunoglobulin G secreting cell balance. J Clin Invest. 1983;71:1342–7.
Acknowledgments
We thank Dr. Shousong Cao and Dr. Meir Wetzler of Roswell Park Cancer Institute (Buffalo, NY, USA) for proofreading the manuscript and for their invaluable suggestions.
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Responsible Editor: Graham Wallace.
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Tang, Y., Peng, Y., Yang, S. et al. Effect of tonsillar mononuclear cell supernatants in patients with IgA nephropathy on renal tubular epithelial cells. Inflamm. Res. 62, 45–52 (2013). https://doi.org/10.1007/s00011-012-0549-0
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DOI: https://doi.org/10.1007/s00011-012-0549-0