Inhibition of STAT3 Signaling Reduces IgA1 Autoantigen Production in IgA Nephropathy.
Kidney Int Rep
; 2(6): 1194-1207, 2017 Nov.
Article
en En
| MEDLINE
| ID: mdl-29270528
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.
Texto completo:
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Colección:
01-internacional
Base de datos:
MEDLINE
Idioma:
En
Revista:
Kidney Int Rep
Año:
2017
Tipo del documento:
Article
País de afiliación:
Estados Unidos