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Serum Amyloid A Activates Nuclear Factor-κB in Rheumatoid Synovial Fibroblasts Through Binding to Receptor of Advanced Glycation End-products HIROSHI OKAMOTO, YUKIKO KATAGIRI, AKIKO KIIRE, SHIGEKI MOMOHARA, and NAOYUKI KAMATANI
ABSTRACT. Methods. Fibroblast-like synovial cells (FLS) were established from RA joints. SAA-stimulated expression of cytokines from FLS was evaluated by ELISA. Nuclear factor-κB (NF-κB) activation by SAA was evaluated by luciferase assay. NF-κB activation and IκBa degradation were evaluated by Western blotting and nuclear localization of p65 subunit of NF-κB in FLS. Expression of receptor for advanced glycation end-products (RAGE) in synovial tissue was evaluated by immunohistochemical study. Effects of preincubation of soluble RAGE on NF-κB activation by SAA was evaluated by Western blotting of IκBa. Results. SAA stimulated the transcriptional activation by NF-κB in a dose-dependent manner and induced expression of the proinflammatory cytokines interleukin 6 (IL-6) and IL-8. Higher expression of RAGE in synovial tissue from patients with RA was noted. SAA induced IκBa degradation, with the peak effect around 30 minutes. Preincubation of SAA with soluble recombinant RAGE protein prevented SAA-induced IκBa degradation. SAA stimulation promoted nuclear translocation of NF-κB, whereas preincubation of SAA with RAGE inhibited nuclear translocation. Conclusion. Our data suggested that the SAA-RAGE-stimulated NF-κB signaling pathway has an important role in the pathogenesis of RA. (First Release Mar 1 2008; J Rheumatol 2008;35:752-6) Key Indexing Terms:
RECEPTOR FOR ADVANCED GLYCATION END-PRODUCT
From the Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan. H. Okamoto, MD, PhD; Y. Katagiri; A. Kiire, MD; S. Momohara, MD, PhD; N. Kamatani, MD, PhD, Institute of Rheumatology, Tokyo Women's Medical University. Address reprint requests to Dr. H. Okamoto, Institute of Rheumatology, Tokyo Women's Medical University, 10-22 Kawada-cho, Shinjuku, Tokyo 162-0054, Japan. E-mail: hokamoto@ior.twmu.ac.jp Accepted for publication December 12, 2007. |
