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.