inhibition of stat3 signaling reduces iga1 autoantigen production in iga nephropathy
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2017
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Abstract
IgA nephropathy is a chronic renal disease characterized by mesangial immunodeposits that contain autoantigen, which is aberrantly glycosylated IgA1 with some hinge-region O-glycans deficient in galactose. Macroscopic hematuria during an upper respiratory tract infection is common among patients with IgA nephropathy, which suggests a connection between inflammation and disease activity. Interleukin-6 (IL-6) is an inflammatory cytokine involved in IgA immune response. We previously showed that IL-6 selectively increases production of galactose-deficient IgA1 in IgA1-secreting cells from patients with IgA nephropathy.
Methods: We characterized IL-6 signaling pathways involved in the overproduction of galactose-deficient IgA1. To understand molecular mechanisms, IL-6 signaling was analyzed by kinomic activity profiling and Western blotting, followed by confirmation assays using siRNA knock-down and small-molecule inhibitors.
Results: STAT3 was differentially activated by IL-6 in IgA1-secreting cells from patients with IgA nephropathy compared with those from healthy control subjects. Specifically, IL-6 induced enhanced and prolonged phosphorylation of STAT3 in the cells from patients with IgA nephropathy, which resulted in overproduction of galactose-deficient IgA1. This IL-6−mediated overproduction of galactose-deficient IgA1 could be blocked by small molecule inhibitors of JAK/STAT signaling.
Discussion: Our results revealed that IL-6−induced aberrant activation of STAT3-mediated overproduction of galactose-deficient IgA1. STAT3 signaling pathway may thus represent a new target for disease-specific therapy of IgA nephropathy.
| Reference Key |
yamada2017kidneyinhibition
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| Authors | ;Koshi Yamada;Zhi-Qiang Huang;Milan Raska;Colin Reily;Joshua C. Anderson;Hitoshi Suzuki;Hiroyuki Ueda;Zina Moldoveanu;Krzysztof Kiryluk;Yusuke Suzuki;Robert J. Wyatt;Yasuhiko Tomino;Ali G. Gharavi;Amy Weinmann;Bruce A. Julian;Christopher D. Willey;Jan Novak |
| Journal | Soft matter |
| Year | 2017 |
| DOI |
10.1016/j.ekir.2017.07.002
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| URL | |
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