Kidney International Reports (Nov 2017)

Inhibition of STAT3 Signaling Reduces IgA1 Autoantigen Production in IgA Nephropathy

  • 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

DOI
https://doi.org/10.1016/j.ekir.2017.07.002
Journal volume & issue
Vol. 2, no. 6
pp. 1194 – 1207

Abstract

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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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