Inhibition of STAT3 Signaling Reduces IgA1 Autoantigen Production in IgA Nephropathy.

Abstract

INTRODUCTION:

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.

• 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: Kidney international reports (Kidney Int Rep) Vol. 2 Issue 6 Pg. 1194-1207 (Nov 2017) ISSN: 2468-0249 [Electronic] United States
• PMID: 29270528 (Publication Type: Journal Article)