Blocking of Akt/NF-kappaB signaling by pentoxifylline inhibits platelet-derived growth factor-stimulated proliferation in Brown Norway rat airway smooth muscle cells.
The proliferation of airway smooth muscle cells (ASMC) can cause airway hyperresponsiveness (AHR). It has been reported that platelet-derived growth factor (PDGF) can stimulate the proliferation of ASMC through phosphatidylinositol 3-kinase (PI3 K) signaling pathway, which can activate Akt protein. Activated-Akt can activate downstream signal protein [p70S6 K, nuclear factor (NF)-kappaB, and extracellular signal regulated kinase (ERK)], increasing the cyclin D1 level and suppressing the transcription of p27Kip1 to enable cell cycle entry. This investigation demonstrated that pentoxifylline (PTX) inhibited the PDGF-stimulated proliferation of ASMC by suppressing activation of the Akt/NF-kappaB pathway. ASMC were treated with PTX for 48 h, which attenuated the PDGF-stimulated proliferation of ASMC. PTX and wortmannin, a PI3 K inhibitor, not only inhibited the PDGF-activated phosphorylation of Akt but also suppressed p70S6 K expression and IkappaBalpha degradation, inhibiting nuclear translocation and the DNA binding activity of NF-kappaB. However, PTX did not influence the phosphorylation of ERK1/2. The suppression of p70S6 K by rapamycin did not influence cyclin D1 expression in PDGF-stimulated cells. These data reveal that the down-regulation of the Akt/NF-kappaB signaling pathway by PTX inhibited the proliferation of ASMC. PTX may provide information on the pathogenesis of asthma.
Chiou
Ya-Ling
YL
Institute of Immunology and Microbiology, National Yang-Ming University, Taipei 112, Taiwan.
Shieh
Jeng-Jer
JJ
Lin
Ching-Yuang
CY
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D008297:Male; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000378:metabolism; D010431:Pentoxifylline / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D051381:Rats; D011914:Rats, Inbred BN; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D020123:Sirolimus / Q000494:pharmacology; D000077191:Wortmannin
D000730:Androstadienes; D016328:NF-kappa B; D010726:Phosphodiesterase Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010982:Platelet-Derived Growth Factor; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051058:Oncogene Protein v-akt; D010431:Pentoxifylline; D020123:Sirolimus; D000077191:Wortmannin