2004年5月
Macrophage migration inhibitory factor up-regulates the expression of interleukin-8 messenger RNA in synovial fibroblasts of rheumatoid arthritis patients - Common transcriptional regulatory mechanism between interleukin-8 and interleukin-1 beta
ARTHRITIS AND RHEUMATISM
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- 巻
- 50
- 号
- 5
- 開始ページ
- 1437
- 終了ページ
- 1447
- 記述言語
- 英語
- 掲載種別
- DOI
- 10.1002/art.20190
- 出版者・発行元
- WILEY-LISS
Objective. Interleukin-8 (IL-8) plays an important role in the migration of inflammatory cells into the synovium and joint fluids in rheumatoid arthritis (RA). This study was undertaken to investigate the IL-8 inductive activity of the macrophage migration inhibitory factor (MIF) in RA synovial fibroblasts. The regulatory mechanism of IL-8 was compared with that of IL-1beta.
Methods. MIF-induced IL-8 and IL-1beta transcriptional activation was studied in RA synovial fibroblasts by Northern blot analysis, enzyme-linked immunosorbent assay, and electromobility shift assay. The effect of anti-MIF antibody administration on murine passive collagen-induced arthritis (CIA) was also evaluated by histologic examination and reverse transcriptase-polymerase chain reaction.
Results. MIF up-regulated the IL-8 messenger RNA (mRNA) and protein levels in a dose-dependent manner. The IL-8 mRNA up-regulation started I hour poststimulation by MIF, and reached a maximum level at 6 hours. IL-1beta mRNA was also up-regulated by MIF. The mRNA up-regulation of IL-8 and IL-1beta by MIF was inhibited by 2 tyrosine kinase inhibitors, a protein kinase C (PKC) inhibitor, an activator protein 1 (AP-1) inhibitor, and by an NF-kappaB inhibitor. A cAMP-dependent kinase inhibitor did not inhibit it. MIF enhanced AP-1 and NF-kappaB binding activities in a dose-dependent manner. Passive CIA enhanced mRNA levels of macrophage inflammatory protein 2 and cytokine-induced neutrophil chemoattractants and, moreover, migration and proliferation of inflammatory cells within the synovium, which were suppressed by administration of an anti-MIF antibody.
Conclusion. MIF may play an important role in the migration of inflammatory cells into the synovium of rheumatoid joints via induction of IL-8. MIF upregulates IL-8 and IL-1beta mRNA via tyrosine kinase-, PKC-, AP-1-, and NF-kappaB-dependent pathways.
Methods. MIF-induced IL-8 and IL-1beta transcriptional activation was studied in RA synovial fibroblasts by Northern blot analysis, enzyme-linked immunosorbent assay, and electromobility shift assay. The effect of anti-MIF antibody administration on murine passive collagen-induced arthritis (CIA) was also evaluated by histologic examination and reverse transcriptase-polymerase chain reaction.
Results. MIF up-regulated the IL-8 messenger RNA (mRNA) and protein levels in a dose-dependent manner. The IL-8 mRNA up-regulation started I hour poststimulation by MIF, and reached a maximum level at 6 hours. IL-1beta mRNA was also up-regulated by MIF. The mRNA up-regulation of IL-8 and IL-1beta by MIF was inhibited by 2 tyrosine kinase inhibitors, a protein kinase C (PKC) inhibitor, an activator protein 1 (AP-1) inhibitor, and by an NF-kappaB inhibitor. A cAMP-dependent kinase inhibitor did not inhibit it. MIF enhanced AP-1 and NF-kappaB binding activities in a dose-dependent manner. Passive CIA enhanced mRNA levels of macrophage inflammatory protein 2 and cytokine-induced neutrophil chemoattractants and, moreover, migration and proliferation of inflammatory cells within the synovium, which were suppressed by administration of an anti-MIF antibody.
Conclusion. MIF may play an important role in the migration of inflammatory cells into the synovium of rheumatoid joints via induction of IL-8. MIF upregulates IL-8 and IL-1beta mRNA via tyrosine kinase-, PKC-, AP-1-, and NF-kappaB-dependent pathways.
- リンク情報
- ID情報
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- DOI : 10.1002/art.20190
- ISSN : 0004-3591
- Web of Science ID : WOS:000221340900011