Journal
INTERNATIONAL IMMUNOLOGY
Volume 24, Issue 4, Pages 219-232Publisher
OXFORD UNIV PRESS
DOI: 10.1093/intimm/dxr125
Keywords
collagen; dexamethasone; O-glycan; transforming growth factor; tumor necrosis factor
Categories
Funding
- Japan Society for the Promotion of Science [21790800, 20390234]
- Ministry of Education, Culture, Sports, Science and Technology
- Kanae Foundation for the Promotion of Medical Science
- Study Group on IgAN
- Grants-in-Aid for Scientific Research [23659441, 20390234, 21790800] Funding Source: KAKEN
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IgA nephropathy (IgAN) is characterized by mesangial deposition of IgA1 and galactose-deficient IgA1 is expected to play a pathogenic role. However, the identity of the receptor for IgA1 is still controversial. Hence, the aim of this study was to explore the receptor for galactose-deficient IgA1. Human monoclonal IgA1 was treated with exoglycosidase and FITC-conjugated control, asialo- and agalactosyl-IgA1 was used as a probe to detect the receptor in cultured human mesangial cells. Tumor necrosis factor-alpha or transforming growth factor-beta 1 treatment accelerated IgA1-binding on mesangial cells, and these effects were diminished by the addition of dexamethasone, whereas these changes were not dependent on galactose-deficiency of IgA1. According to comprehensive gene expression analysis, we focused on integrin beta 1. Pre-treatment by Mn2+, which activates integrin by changing its structure, enhanced the binding of IgA1 in cultured mesangial cells. Furthermore, pre-incubation with collagens specifically enhanced binding of IgA1 in the cultured human mesangial cells without activation by Mn2+. Collagen type IV distributed in the mesangial region of the glomeruli as well as Bowman's capsule and tubular basal membrane in IgAN patients, and the IgA1 with collagen type IV induced proliferative signals on mesangial cells by phosphorylating extracellular signal-regulated kinase more effectively than the IgA1 alone. Immunoprecipitation assay revealed the binding of IgA1 and integrin alpha 1/beta 1 and alpha 2/beta 1 heterodimer and down-regulation of integrin alpha 1, alpha 2 and beta 1 expression in human mesangial cells induced by each specific small interfering RNA diminished the ability to bind IgA1 probe. Integrin alpha 1/beta 1 and alpha 2/beta 1 would be a candidate receptor for IgA1.
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