Abstract：
:A new experimental drug pirfenidone (5-methyl-1-phenyl-2-1H-pyridine-2-one) has been reported to have beneficial effects for the treatment of certain fibrotic diseases. Here, we studied the anti-inflammatory activities of pirfenidone by investigating the mechanism of its inhibitory effect on cytokine production. In RAW264.7 cells, a murine macrophage-like cell line, pirfenidone suppressed the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) by a translational mechanism, which was independent of activation of the mitogen-activated protain kinase (MAPK) 2, p38 MAP kinase, and c-Jun N-terminal kinase (JNK). In the murine endotoxin shock model, pirfenidone potently inhibited the production of the proinflammatory cytokines, TNF-alpha, interferon-gamma, and interleukin-6, but enhanced the production of the anti-inflammatory cytokine, interleukin-10. The in vivo model also showed that pirfenidone suppressed the cytokine production by a translational mechanism, though interleukin-10 transcription was activated by pirfenidone. These findings show that pirfenidone inhibits the production of the proinflammatory cytokine selectively at the translational level. Therefore, cytokine inhibitory activities play an important role in the anti-inflammatory activities of pirfenidone. Coupled with the fact that this inhibitory effect is selective, translational, and not for total protein synthesis, this drug may have a clinical effect on inflammation and fibrosis with very low toxicity.
journal_name
Eur J Pharmacoljournal_title
European journal of pharmacologyauthors
Nakazato H,Oku H,Yamane S,Tsuruta Y,Suzuki Rdoi
10.1016/s0014-2999(02)01758-2keywords:
subject
Has Abstractpub_date
2002-06-20 00:00:00pages
177-85issue
1-3eissn
0014-2999issn
1879-0712pii
S0014299902017582journal_volume
446pub_type
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