4, TOMINO selleck inhibitor YASUHIKO2, GHARAVI ALI G.5, JULIAN BRUCE A.1, WILLEY CHRISTOPHER D.1, NOVAK JAN1 1University of Alabama at Birmingham, Birmingham, AL, USA; 2Juntendo University Faculty of Medicine, Tokyo, Japan; 3Palacky University, Olomouc, Czech Republic; 4University of Tennessee, Memphis, TN, USA; 5Columbia University, New York, NY, USA Introduction: IgAN is an autoimmune disease characterized by IgA1-containing mesangial deposits. These deposits are likely derived from circulating
immune complexes formed from IgA1 with galactose-deficient O-glycans (Gd-IgA1; autoantigen) and anti-glycan autoantibodies. Macroscopic hematuria in IgAN patients often coincides with mucosal infections, including infections of the upper respiratory tract and/or digestive
system that may dramatically change the cytokine milieu. For example, IL-6 can be secreted by macrophages Vincristine cost in response to specific microbial molecules, such as lipopolysaccharides, or bacterial and viral DNA, and it has been shown that serum IL-6 is elevated in some IgAN patients. We have demonstrated that IL-6 increases production of Gd-IgA1 by IgA1-secreting cells from IgAN patients. Here, we characterize IL-6 signaling pathways involved in the enhanced production of Gd-IgA1. Methods: IgA1-secreting cells derived from the circulation and tonsils of IgAN patients and healthy controls (HC) were stimulated with IL-6; IgA1 and Gd-IgA1were measured by ELISA. IL-6/JAK/STAT3 signaling pathways were analyzed by kinome profiling using PamStation® 12 PTK (tyrosine kinome PamChip) and Western blotting,
and the conclusions confirmed by using siRNA knock-down and specific inhibitors. Results: IL-6 stimulation induced a more robust and prolonged STAT3 phosphorylation in cells from IgAN patients than those from HC. siRNA knock-down and some protein-kinase inhibitors Thalidomide confirmed the central role of STAT3 activation in the enhanced production of Gd-IgA1 in response to IL-6 (P < 0.05). Kinome profiling confirmed an abnormal IL-6/STAT3 signaling pathway in the cells from IgAN patients (p < 4.95 × 10−6). Conclusion: IL-6-mediated activation of STAT3 plays an important role in the enhanced production of Gd-IgA1 in IgAN. Thus, IL-6/STAT3 signaling may offer a new target for future disease-specific therapy. INOSHITA HIROYUKI1,2, KIM BYUNG-GYU3, YAMASHITA MICHIFUMI2,4, CHOI SUNG HEE3, TOMINO YASUHIKO1, LETTERIO JOHN J.3, EMANCIPATOR STEVEN N.2 1Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine; 2Department of Pathology, Case Western Reserve University; 3Department of Pediatrics, Case Western Reserve University; 4Department of Pathology, University Hospitals Case Medical Center Introduction: The association between IgA nephropathy (IgAN) and T helper 2 (Th2) response has been indicated by many reports. However, the mechanisms are poorly understood because of the lack of an appropriate model.