Journal
NEPHROLOGY DIALYSIS TRANSPLANTATION
Volume 25, Issue 12, Pages 3890-3897Publisher
OXFORD UNIV PRESS
DOI: 10.1093/ndt/gfq325
Keywords
IgA1 hinge region; T-cell cytokines; the surface IgA1-positive human B-cell line; Th2 response
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Funding
- study group on IgA nephropathy in Japan
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Background. Patients with IgA nephropathy (IgAN) have an increased amount of abnormally O-glycosylated IgA1 in circulation, in glomerular deposits and produced by tissue cells in vitro. Although increased production of Th2 cytokines by peripheral blood lymphocytes and a functional abnormality of core 1 beta 1,3-galactosyltransferase (C1 beta 3Gal-T) have been proposed as mechanisms underlying pathogenesis of IgAN, they are still obscure and are not connected. Methods. To clarify the effect of T-cell cytokines, we analysed the mRNA levels of C1 beta 3Gal-T and its molecular chaperone Cosmc, C1 beta 3Gal-T activity and subsequent O-glycosylation of IgA1 in a human B-cell line stimulated with these cytokines. The surface IgA1-positive human B-cell line was cultured with recombinant human IFN-gamma, IL-2, IL-4 or IL-5. The production and glycosylation of IgA1 were determined by sandwich ELISA and enzyme-linked lectin binding assay, respectively. The mRNA levels of C1 beta 3Gal-T and Cosmc were quantitatively measured by real-time PCR. C1 beta 3Gal-T activity was analysed using high-performance liquid chromatography. Results. IgA1 production by IL-4-stimulated cells was significantly higher than controls or after IFN-gamma or IL-5. The terminal glycosylation of secreted IgA1 was altered in response to IL-4. IL-4 stimulation significantly decreased the mRNA levels of both C1 beta 3Gal-T and Cosmc and of C1 beta 3Gal-T activity. IL-4 stimulation was clearly blocked by recombinant human IL-4 soluble receptor. Conclusions. It appears that Th2 cytokine IL-4 may play a key role in controlling glycosylation of the IgA1 hinge region.
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