IL-33 regulates TNF-α dependent effects in synovial fibroblasts

被引:61
作者
Kunisch, Elke [1 ]
Chakilam, Saritha [1 ,2 ]
Gandesiri, Muktheshwar [1 ,2 ]
Kinne, Raimund W. [1 ]
机构
[1] Univ Hosp Jena, Dept Orthoped, Expt Rheumatol Unit, D-07607 Eisenberg, Germany
[2] Univ Erlangen Nurnberg, Inst Pathol, D-91054 Erlangen, Germany
关键词
fibroblasts; interleukin-33; TNF-alpha; inflammatory diseases; IL-1-LIKE CYTOKINE IL-33; RHEUMATOID-ARTHRITIS; MAST-CELLS; KAPPA-B; PRIMARY-CULTURE; MESSENGER-RNA; ST2; RECEPTOR; IN-VIVO; ACTIVATION; INHIBITION;
D O I
10.3892/ijmm.2012.883
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
The recently described IL-33 acts as a proinflammatory cytokine, inducing the expression of multiple responses in the target cells. Although a nuclear localization of IL-33 has been described, its exact functional relevance is presently unknown. The present study was conducted to analyze the effects of IL-33 on the TNF-alpha induced synthesis of the pro-inflammatory mediators IL-6, IL-8, and monocyte chemotactic protein-1 (MCP-1) and the pro-destructive molecules matrix metalloproteinase-1 (MMP-1), MMP-3, and TIMP-1 of rheumatoid arthritis synovial fibroblast (RA-SFs) using RNA overexpression and silencing. TNF-a significantly induced IL-33 mRNA expression and protein synthesis in RA-SFs. TNF-alpha-induced IL-33 protein expression was mediated via p38 signaling. Immunohistochemistry for IL-33 clearly showed that nuclear translocation of IL-33 was induced in TNF-alpha stimulated RA-SFs. IL-33 overexpression enhanced TNF-alpha-induced pro-inflammatory and pro-destructive functions in RA-SFs. IL-33 silencing significantly downregulated TNF-alpha-induced pro-inflammatory functions, whereas TNF-alpha-induced pro-destructive functions were less influenced by IL-33 silencing. This study identifies IL-33 as a critical regulator/enhancer of TNF-alpha-induced functions in RA-SFs, pointing to a central role of this cytokine in the perpetuation of pro-inflammatory and pro-destructive processes in rheumatoid arthritis (RA) and other inflammatory and degenerative diseases.
引用
收藏
页码:530 / 540
页数:11
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