inhibition of stat3 signaling reduces iga1 autoantigen production in iga nephropathy

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ID: 183378
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.
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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
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Journal Soft matter
Year 2017
DOI
10.1016/j.ekir.2017.07.002
URL
http://www.sciencedirect.com/science/article/pii/S2468024917303005
Keywords
iga nephropathy urology

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