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‐1β

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Abstract
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‐1β.Methods: MIF‐induced IL‐8 and IL‐1β 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 1 hour poststimulation by MIF, and reached a maximum level at 6 hours. IL‐1β mRNA was also up‐regulated by MIF. The mRNA up‐regulation of IL‐8 and IL‐1β 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‐κB inhibitor. A cAMP‐dependent kinase inhibitor did not inhibit it. MIF enhanced AP‐1 and NF‐κB 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 up‐regulates IL‐8 and IL‐1β mRNA via tyrosine kinase–, PKC‐, AP‐1–, and NF‐κB–dependent pathways.