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Cytokines alter IgA1 O-glycosylation by dysregulating C1GalT1 and ST6GalNAc-II enzymes.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2014 Feb 21; Vol. 289 (8), pp. 5330-9. Date of Electronic Publication: 2014 Jan 07. - Publication Year :
- 2014
-
Abstract
- IgA nephropathy (IgAN), the most common primary glomerulonephritis, is characterized by renal immunodeposits containing IgA1 with galactose-deficient O-glycans (Gd-IgA1). These immunodeposits originate from circulating immune complexes consisting of anti-glycan antibodies bound to Gd-IgA1. As clinical disease onset and activity of IgAN often coincide with mucosal infections and dysregulation of cytokines, we hypothesized that cytokines may affect IgA1 O-glycosylation. We used IgA1-secreting cells derived from the circulation of IgAN patients and healthy controls and assessed whether IgA1 O-glycosylation is altered by cytokines. Of the eight cytokines tested, only IL-6 and, to a lesser degree, IL-4 significantly increased galactose deficiency of IgA1; changes in IgA1 O-glycosylation were robust for the cells from IgAN patients. These cytokines reduced galactosylation of the O-glycan substrate directly via decreased expression of the galactosyltransferase C1GalT1 and, indirectly, via increased expression of the sialyltransferase ST6GalNAc-II, which prevents galactosylation by C1GalT1. These findings were confirmed by siRNA knockdown of the corresponding genes and by in vitro enzyme reactions. In summary, IL-6 and IL-4 accentuated galactose deficiency of IgA1 via coordinated modulation of key glycosyltransferases. These data provide a mechanism explaining increased immune-complex formation and disease exacerbation during mucosal infections in IgAN patients.
- Subjects :
- Adult
Cell Line
Female
Galactose deficiency
Galactose metabolism
Gene Knockdown Techniques
Glomerulonephritis, IGA enzymology
Glomerulonephritis, IGA pathology
Glycosylation drug effects
Humans
Interleukin-4 pharmacology
Interleukin-6 pharmacology
Male
N-Acetylneuraminic Acid metabolism
Polysaccharides metabolism
RNA, Small Interfering metabolism
Cytokines pharmacology
Galactosyltransferases metabolism
Immunoglobulin A metabolism
Sialyltransferases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 289
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 24398680
- Full Text :
- https://doi.org/10.1074/jbc.M113.512277