期刊
RHEUMATOLOGY
卷 50, 期 5, 页码 838-851出版社
OXFORD UNIV PRESS
DOI: 10.1093/rheumatology/keq380
关键词
Osteoarthritis; Advanced glycation end products; Receptor for advanced glycation end product; mitogen-activated protein kinases; nuclear factor-kappa B; Interleukin-6; Interleukin-8
类别
资金
- National Institutes of Health [RO1-AT-003267, RO1-AT-005520, R21-AT504615]
- MetroHealth Medical Center, Cleveland, OH, USA
Methods. OA chondrocytes were stimulated with AGE-modified BSA (AGE-BSA). Gene expression of IL-6 and IL-8 was quantified by TaqMan assays and the production was determined using ELISAs. Immunoblotting was used to analyse the activation of mitogen-activated protein kinases (MAPKs) and the degradation of I kappa B alpha. Activation of NF-kappa B was determined using an ELISA. Pharmacological studies to elucidate the involved pathways were executed using transfection with small interfering RNAs (siRNAs), inhibitors of MAPKs and NF-kappa B. Results. AGE-BSA induced the expression of IL-6 and IL-8 in OA chondrocytes, which was inhibited by pre-treatment with soluble RAGE (sRAGE) or RAGE knockdown by siRNAs. Treatment with SB202190 (p38-MAPK inhibitor) or PD98059 (ERK inhibitor) inhibited AGE-BSA-induced IL-6 and IL-8 expression. However, SP600125 (JNK inhibitor) had no effect on AGE-BSA-induced IL-6 expression but inhibited the expression of IL-8. Treatment with NF-kappa B inhibitors suppressed AGE-BSA-induced IL-6 and IL-8 expression. Conclusions. This is the first study to demonstrate that AGEs induce the expression of IL-6 and IL-8 in OA chondrocytes. A novel finding of our studies is that in OA chondrocytes, AGE-BSA-induced expression of IL-6, but not of IL-8, was independent of the JNK pathway. Activation of NF-kappa B was an absolute requirement for both IL-6 and IL-8 expression. These results demonstrate that AGE-BSA-induced expression of IL-6 and IL-8 via RAGE is mediated through different MAPK signalling pathways in OA and possibly in other degenerative diseases.
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