Administration of PDE4 Inhibitors Suppressed the Pannus-Like Inflammation by Inhibition of Cytokine Production by Macrophages and Synovial Fibroblast Proliferation
A marked proliferation of synovial fibroblasts in joints leads to pannus formation in rheumatoid arthritis (RA). Various kinds of cytokines are produced in the pannus. The purpose of this study is to elucidate the effects of phosphodiesterase 4 (PDE4) inhibitors in a new animal model for the e...
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| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2007-01-01
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| Series: | Mediators of Inflammation |
| Online Access: | http://dx.doi.org/10.1155/2007/58901 |
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| Summary: | A marked proliferation of synovial fibroblasts in joints leads to pannus formation
in rheumatoid arthritis (RA). Various kinds of cytokines are produced in the pannus. The
purpose of this study is to elucidate the effects of phosphodiesterase 4 (PDE4) inhibitors
in a new animal model for the evaluation of pannus formation and cytokine production
in the pannus. Mice sensitized with methylated bovine serum albumin (mBSA) were
challenged by subcutaneous implantation of a membrane filter soaked in mBSA solution
in the back of the mice. Drugs were orally administered for 10 days. The granuloma
formed around the filter was collected on day 11. It was chopped into pieces and
cultured in vitro for 24 hr. The cytokines were measured in the supernatants. The type
of cytokines produced in the granuloma was quite similar to those produced in pannus
in RA. Both PDE4 inhibitors, KF66490 and SB207499, suppressed the production
of IL-1β, TNF-α, and IL-12, and the increase in myeloperoxidase activity, a marker enzyme
for neutrophils and hydroxyproline content. Compared to leflunomide, PDE4 inhibitors
more strongly suppressed IL-12 production and the increase in myeloperoxidase
activity. PDE4 inhibitors also inhibited lipopolysaccharide-induced TNF-α and IL-12 production from thioglycolate-induced murine peritoneal
macrophages and the proliferation of rat synovial fibroblasts. These results indicate
this model makes it easy to evaluate the effect of drugs on various cytokine productions
in a granuloma without any purification step and may be a relevant model for evaluating
novel antirheumatic drugs on pannus formation in RA. PDE4 inhibitors could have
therapeutic effects on pannus formation in RA by inhibition of cytokine production
by macrophages and synovial fibroblast proliferation. |
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| ISSN: | 0962-9351 1466-1861 |