EM703, a new derivative of erythromycin, inhibits transforming growth factor-beta signaling in human lung fibroblasts.
Long-term, low-dose macrolide therapy has been proven to improve survival in patients with diffuse panbronchiolitis and cystic fibrosis, although the mechanisms by which it does so remain unknown. To elucidate the molecular mechanisms of the anti-inflammatory effects of macrolides, the authors examined the effects of erythromycin (EM-A) and new derivative EM703 on transforming growth factor (TGF)-beta /Smad signaling fibroblasts. EM-A and EM703 each inhibited fibroblast proliferation and the collagen production in human lung fibroblasts induced by TGF-beta. EM-A and EM703 inhibited the augmentation of Smad3 mRNA induced by TGF-beta. Smad7 mRNA was inhibited by TGF-beta, but augmented by coincubation with EM-A or EM703. EM-A and EM703 each inhibited p-Smad2/3 proteins induced by TGF-beta. Smad7 protein inhibited by TGF-beta restored beyond basal level by EM-A and EM703. These findings suggest that EM-A and EM703 inhibit TGF-beta signaling in human lung fibroblasts via inhibition of p-Smad2/3 through recovery of Smad7 level.
Yu
ChangHe
C
Department of Internal Medicine-Pulmonary Medicine, Infection, and Oncology, Nippon Medical School, Tokyo, Japan.
Azuma
Arata
A
Li
YingJi
Y
Wang
Chunyan
C
Abe
Sinji
S
Usuki
Jiro
J
Matsuda
Kuniko
K
Kudoh
Shoji
S
Sunazuka
Toshiaki
T
Omura
Satoshi
S
D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000933:Antifibrinolytic Agents / Q000494:pharmacology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D004338:Drug Combinations; D004917:Erythromycin / Q000031:analogs & derivatives* / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D000900:Anti-Bacterial Agents; D000933:Antifibrinolytic Agents; D004338:Drug Combinations; C509870:EM703; D012333:RNA, Messenger; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D004917:Erythromycin; D003094:Collagen