A novel anti-fibrotic agent pirfenidone suppresses tumor necrosis factor-alpha at the translational level.
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.
Nakazato
Hitoshi
H
Department of Immunology, Shionogi Discovery Research Laboratories, Shionogi & Co. Ltd., 2-5-1, Mishima, Settsu, Osaka 566-0022, Japan.
Oku
Hisashi
H
Yamane
Shoji
S
Tsuruta
Yuji
Y
Suzuki
Ryuji
R
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D015152:Blotting, Northern; D002460:Cell Line; D005260:Female; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D048031:JNK Mitogen-Activated Protein Kinases; D008070:Lipopolysaccharides; D048370:MAP Kinase Kinase 2; D051379:Mice; D008810:Mice, Inbred C57BL; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D014176:Protein Biosynthesis; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011728:Pyridones / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012772:Shock, Septic / Q000209:etiology / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases; D000093242:Interleukin-6 Inhibitors
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007371:Interferon-gamma; D016753:Interleukin-10; D015850:Interleukin-6; D048031:JNK Mitogen-Activated Protein Kinases; D008070:Lipopolysaccharides; D048370:MAP Kinase Kinase 2; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D011505:Protein-Tyrosine Kinases; D011728:Pyridones; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D000093242:Interleukin-6 Inhibitors; C093844:pirfenidone